Cycloolefin substituted heteroaromatic compounds and their use

ABSTRACT

Compounds of formula (I) or a pharmaceutically acceptable salt thereof, and/or solvates racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein A, R1, R2, R3, R3′, R4, R4′, R5, R6, R7, R8, m, and n are as defined in the detailed description.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 16/645,329, filed on Mar. 6, 2020, which is aUnited States application under 35 U.S.C. 371 of InternationalApplication No. PCT/CN2018/104531, filed on Sep. 7, 2018, which claimsbenefit of Chinese Patent Application No. 201710801364.3, filed on Sep.7, 2017, the contents of each of which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to cycloolefin substituted heteroaromaticcompounds and their use in the treatment of diseases induced by IDHmutations.

BACKGROUND OF THE INVENTION

The survival way of tumor cells is different from that of normal cells,so does the energy intake and utilization. The common metabolic pathwayin aerobic organisms is tricarboxylic acid cycle, in which isocitratedehydrogenase (IDH) catalyzing the conversion of isocitrate toα-ketoglutaric acid (α-KG) is a rate-limiting step. The known IDH familycomprises three isozymes, IDH1, IDH2 and IDH3, which are located indifferent organelles and perform the same biological functions, i.e.,catalyzing the formation of α-KG. Recent studies have shown thatheterozygous IDH1/2 mutations were present in a certain proportion of avariety of tumors, such as glioma (60-80%), chondrosarcoma (55%), acutemyeloid leukemia (15-25%), etc. The mutant IDH1 or IDH2 loses thecapability of catalyzing the conversion of isocitrate to α-KG, whereashas the ability of catalyzing the reaction of α-KG to α-hydroxyglutaricacid (2-HG). As the structure of 2-HG is similar to the structure ofα-KG, 2-HG can competitively inhibit the activity of many α-KG dependentenzymes (for example: histone demethylase and methylcytosine hydroxylaseof the TET family, and the like) when it accumulates to a certainextent, and thus effects the demethylation of histones and DNA,interferes with normal cell differentiation, and results in theproliferation of immature cells.

Agios Pharmaceuticals published its research results in Science magazinein 2013: the mutant IDH1 enzyme inhibitor AGI-5198 (Science, 2013, 340,626-630) and the mutant IDH2 enzyme inhibitor AGI-6780 (Science, 2013,340, 622-626) developed by the company can effectively inhibit thegeneration of 2HG mediated by mutant IDH1/IDH2 in cells and can inducedifferentiation of abnormally proliferating cancer cells. Both thetreatment of glioma cells harboring mutant IDH1 gene with AGI-5198 andthe treatment of leukemia cells carrying mutant IDH2 gene with AG-6780lead to increase of the expression of mature markers in cells.

The Phase I clinical trial of AG-120, a mutant IDH1 inhibitor developedby Agios Pharmaceuticals, showed that in patients with acute myeloidleukemia (AML) or myelodysplastic syndrome (MDS) having IDH1 mutations,it can be observed that 98% of the patients have decreased levels ofα-hydroxyglutaric acid (2HG).

Acute myeloid leukemia (AML) is one of the most difficult diseases to becontrolled in common hematological malignancies. Its recurrence rate ishigh. The development of new drug for the disease is slow resulting inthe lack of effective drug therapy. Some studies have shown that about15% of the patients with acute myeloid leukemia have IDH2 genemutations. Enasidenib (former name AG-221), a mutant IDH2 inhibitor,developed by Agios Pharmaceuticals and Celgene, showed a significanteffect on relapsed and refractory acute myelogenous leukemias with IDH2gene mutations in clinical trial.

New IDH mutant inhibitors are needed to be developed to meet the needfor treatment of patients with hematological tumors, especially acutemyeloid leukemia, gliomas and other IDH mutation associated tumors. Thepresent invention addresses these needs.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (I):

and/or a pharmaceutically acceptable salt thereof, and/or solvates,racemic mixtures, enantiomers, diasteromers, and tautomers thereof,wherein A, R₁, R₂, R₃, R_(3′), R₄, R_(4′), R₅, R₆, R₇, R₈, m, and n areas defined in the detailed description of the invention.

Also provided is a pharmaceutical composition, comprising at least onecompound of formula (I) (e.g., any of the compounds described herein)and/or a pharmaceutically acceptable salt thereof, and optionallycomprising at least one pharmaceutically acceptable excipient (e.g., apharmaceutically acceptable carrier).

Also provided is a method of treating a disease induced by IDH mutation,comprising administering to the subject in need thereof an effectiveamount of at least one compound of formula (I) (e.g., any of thecompounds described herein) and/or at least one pharmaceuticallyacceptable salt thereof.

Also provided is a use of at least one compound of formula (I) (e.g.,any of the compounds described herein) and/or at least onepharmaceutically acceptable salt thereof for treating a disease inducedby IDH mutation.

Also provided is a use of at least one compound of formula (I) (e.g.,any of the compounds described herein) and/or at least onepharmaceutically acceptable salt thereof in the manufacture of amedicament for treating a disease induced by IDH mutation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the general synthetic route I for preparation of thecompounds described herein.

FIG. 2 shows the general synthetic route II for preparation of thecompounds described herein.

FIG. 3 shows the general synthetic route III for preparation of thecompounds described herein.

FIG. 4 shows the general synthetic route IV for preparation of thecompounds described herein.

FIG. 5 shows the general synthetic route V for preparation of thecompounds described herein.

FIG. 6 shows the general synthetic route VI for preparation of thecompounds described herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used in the present application, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —OR₄ isattached through the oxygen. However, when the point of attachment of agroup is apparent to those skilled in the art, e.g., a halo substituent,the “-” sign may be omitted.

Unless clearly indicated otherwise, use of the terms “a”, “an” and thelike refer to one or more.

The term “alkyl” as used herein refers to a straight or branchedsaturated hydrocarbon radical containing 1-18 carbon atoms, preferably1-10 carbon atoms, more preferably 1-6 carbon atoms, and even morepreferably 1-4 carbon atoms. For example, “C₁₋₆ alkyl” refers to analkyl containing 1-6 carbon atoms. Examples of alkyl groups include, butare not limited to, methyl (“Me”), ethyl (“Et”), n-propyl (“n-Pr”),i-propyl (“i-Pr”), n-butyl (“n-Bu”), i-butyl (“i-Bu”), s-butyl (“s-Bu”)and t-butyl (“t-Bu”).

The term “alkenyl” as used herein refers to a straight or branchedhydrocarbon radical containing one or more, for example 1, 2, or 3carbon-carbon double bonds (C═C) and 2-10 carbon atoms, preferably 2-6carbon atoms, more preferably 2-4 carbon atoms. For example, “C₂₋₆alkenyl” refers to an alkenyl containing 2-6 carbon atoms. Examples ofalkenyl groups include, but are not limited to, vinyl, 2-propenyl, and2-butenyl. The point of attachment for the alkenyl can be on or not onthe double bonds.

The term “alkynyl” as used herein refers to a straight or branchedhydrocarbon radical containing one or more, for example 1, 2, or 3,carbon-carbon triple bonds (C≡C) and 2-10 carbon atoms, preferably 2-6carbon atoms, more preferably 2-4 carbon atoms. For example, “C₂₋₆alkynyl” refers to an alkynyl containing 2-6 carbon atoms. Examples ofalkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and2-butynyl. The point of attachment for the alkynyl can be on or not onthe triple bonds.

The term “halogen” or “halo” as used herein means fluoro, chloro, bromo,and iodo, preferably fluoro, chloro and bromo, more preferably fluoroand chloro.

The term “haloalkyl” as used herein refers to an alkyl radical, asdefined herein, in which one or more, for example 1, 2, 3, 4, or 5,hydrogen atoms are replaced with halogen atom, and when more than onehydrogen atoms are replaced with halogen atoms, the halogen atoms may bethe same or different from each other. In certain an embodiment, theterm “haloalkyl” as used herein refers to an alkyl radical, as definedherein, in which two or more, such as 2, 3, 4, or 5 hydrogen atoms arereplaced with halogen atoms, wherein the halogen atoms are identical toeach other. In another embodiment, the term “haloalkyl” as used hereinrefers to an alkyl radical, as defined herein, in which two or morehydrogen atoms, such as 2, 3, 4, or 5 hydrogen atoms are replaced withhalogen atoms, wherein the halogen atoms are different from each other.Examples of haloalkyl groups include, but are not limited to, —CF₃,—CHF₂, —CH₂CF₃, and the like.

The term “alkoxy” as used herein refers to the group —O-alkyl, whereinthe alkyl is as defined above. Examples of alkoxy groups include, butare not limited to, C₁₋₆ alkoxy, such as methoxy, ethoxy, n-propyloxy,i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, andhexyloxy, including their isomers.

The term “cycloalkyl” as used herein refers to saturated or partiallyunsaturated cyclic hydrocarbon radical having 3 to 12 ring carbon atoms,such as 3 to 8 ring carbon atoms, 5-7 ring carbon atoms, 4-7 ring carbonatoms or 3 to 6 ring carbon atoms, which may have one or more rings,such as 1, 2, or 3 rings, preferably 1 or 2 rings. For example, “C₃₋₁₂cycloalkyl” refers to a cycloalkyl containing 3-12 carbon atoms in thering. “Cycloalkyl” also includes a fused or bridged ring, or aspirocyclic ring. The rings of the cycle group may be saturated or hasone or more, for example, one or two double bonds (i.e. partiallyunsaturated), but not fully conjugated, and not an aryl as definedherein. Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[4.1.0]heptyl, bicyclo[3.1.1]heptyl,spiro[3.3]heptyl, spiro[2.2]pentyl, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, and bicyclo[3.1.1]hepta-2-ene.

The term “heterocycle”, “heterocyclyl” or “heterocyclic” as used hereinrefers to monocyclic, bicyclic or tricyclic saturated or partiallyunsaturated cyclic radicals having 3-12 ring atoms, such as 3-8 ringatoms, 5-7 ring atoms, 4-7 ring atoms or 3-6 ring atoms, and containingone or more, for example 1, 2 or 3, preferably 1 or 2 heteroatomsindependently chosen from N, O and S in the rings, with the remainingring atoms being carbon. The heterocycle group also includes thosewherein the N or S heteroatom are optionally oxidized to variousoxidation states. The point of attachment of heterocyclyl can be on theN heteroatom or carbon. For example, “3-8 membered heterocycly” refersto a heterocyclyl containing 3-8 ring atoms and containing at least oneheteroatom independently chosen from N, O and S.

The heterocycle group also includes a fused or bridged ring, or aspirocyclic ring, wherein, at least one ring contains at least oneheteroatom chosen from O, S, and N and none of the other rings is arylor heteroaryl as defined herein. The rings of the heterocycle group maybe saturated or has one or more, for example, one or two double bonds(i.e. partially unsaturated), but not fully conjugated, and not aheteroaryl as defined herein. Examples of heterocycly groups include,but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl,tetrahydrofuryl, dioxolaneyl, morpholinyl, thiomorpholinyl, piperidyl,piperazinyl, pyrazolidinyl, and oxaspiro[3.3]heptanyl.

The term “aryl” as used herein refers to carbocyclic hydrocarbon radicalof 6 to 14 carbon atoms consisting of one ring or more fused rings,wherein at least one ring is an aromatic ring. Examples of aryl groupsinclude, but are not limited to, phenyl, naphthalenyl,1,2,3,4-tetrahydronaphthalenyl, indenyl, indanyl, azulenyl, preferablyphenyl and naphthalenyl.

The term “heteroaryl” as used herein refers to:

-   -   monocyclic aromatic hydrocarbon radical having 5, 6 or 7 ring        atoms, preferably having 6 ring atoms, and containing one or        more, for example 1, 2 or 3, preferably 1 or 2 heteroatoms        independently chosen from N, O, and S (preferably N) in the        ring, with the remaining ring atoms being carbon; and    -   bicyclic aromatic hydrocarbon radical having 8-12 ring atoms,        preferably having 9 or 10 ring atoms, and containing one or        more, for example, 1, 2, 3 or 4, preferably 2, 3 or 4        heteroatoms independently chosen from N, O, and S (preferably N)        in the rings, with the remaining ring atoms being carbon,        wherein at least one of the rings is aromatic. For example, the        bicyclic heteroaryl includes a 5- to 6-membered heterocyclic        aromatic ring fused to a 5- to 6-membered cycloalkyl ring.

When the total number of S and O atoms in the heteroaryl group exceeds1, said S and O heteroatoms are not adjacent to one another.

The heteroaryl group also includes those wherein the N heteroatom occursas N-oxide, such as pyridyl N-oxides.

Examples of the heteroaryl group include, but are not limited to,pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl,triazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyridazinyl,benzodioxolyl, benzooxazolyl, benzoisoxazolyl, benzothienyl,benzothiazolyl, benzoisothiazolyl, imidazopyridyl (such asimidazo[1,2-a]pyridyl), pyrrolopyridyl, pyrrolopyrimidinyl,pyrazolopyridinyl (such as pyrazolo[1,5-a]pyridyl), pyrazolopyrimidinyl,triazolopyridinyl (such as [1,2,4]triazolo[1,5-a]pyridyl),tetrazolopyridinyl, tetrahydropyrazolopyridyl (such as4,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, benzofuryl, benzoimidazolinyl,indolyl, indazolyl, purinyl, quinolinyl, and isoquinolinyl.

“Hydroxyl” as used herein refers to the —OH radical.

“Mercapto” as used herein refers to the —SH radical.

“Oxo” as used herein refers to the ═O radical.

When a structure herein contains an asterisk “*”, it means that thechiral center of the compound marked by “*” is in either R-configurationor S-configuration, and the content of the compound with singleconfiguration marked by “*” is at least 90% (e.g., 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%, or any value betweenthose enumerated values). The configuration of the compounds can bedetermined using a variety of analytical techniques, for example singlecrystal X-ray crystallography and/or optical polarimetry according toroutine protocols by those of ordinary skill in the art.

When a structure herein contains “(RS)”, it means that the chiral centerof the compound marked by “(RS)” contains both R-configuration andS-configuration.

The term “optional” or “optionally” as used herein means that thesubsequently described event or circumstance may or may not occur, andthe description includes instances wherein the event or circumstanceoccur and instances in which it does not occur. For example, “optionallysubstituted alkyl” encompasses both “unsubstituted alkyl” and“substituted alkyl” as defined herein. It will be understood by thoseskilled in the art, with respect to any group containing one or moresubstituents, that such groups are not intended to introduce anysubstitution or substitution patterns that are sterically impractical,chemically incorrect, synthetically non-feasible and/or inherentlyunstable.

The term “substituted” or “substituted with . . . ”, as used herein,means that one or more hydrogens on the designated atom or group arereplaced with one or more selections from the indicated group ofsubstituents, provided that the designated atom's normal valence is notexceeded. When a substituent is oxo (i.e., ═O), then 2 hydrogens on asingle atom are replaced by the oxo. Combinations of substituents and/orvariables are permissible only if such combinations result in achemically correct and stable compound. A chemically correct and stablecompound is meant to imply a compound that is sufficiently robust tosurvive sufficient isolation from a reaction mixture to be able toidentify the chemical structure of the compound, and also sufficientlyrobust to allow subsequent formulation as an agent having at least onepractical utility.

Unless otherwise specified, substituents are named into the corestructure. For example, it is to be understood that when(cycloalkyl)alkyl is listed as a possible substituent, the point ofattachment of this substituent to the core structure is in the alkylportion.

The term “substituted with one or more substitutents” as used hereinmeans that one or more hydrogens on the designated atom or group areindependently replaced with one or more selections from the indicatedgroup of substituents. In some embodiments, “substituted with one ormore substitutents” means that the designated atom or group issubstituted with 1, 2, 3, or 4 substitutents independently chosen fromthe indicated group of substituents.

It will be appreciated by the person of ordinary skill in the art(“POSITA”) that some of the compounds of formula (I) may contain one ormore chiral centers and therefore exist in two or more stereoisomericforms. The racemates of these isomers, the individual isomers andmixtures enriched in one enantiomer, as well as diastereomers when thereare two chiral centers, and mixtures partially enriched with specificdiastereomers are within the scope of the present invention. It will befurther appreciated by the POSITA that the present invention includesall the individual stereoisomers (e.g. enantiomers), racemic mixtures orpartially resolved mixtures of the compounds of formula (I) and, whereappropriate, the individual tautomeric forms thereof.

In other words, in some embodiments, the present invention providescompounds of various stereoisomeric purities, i.e., diastereomeric orenantiomeric purity expressed as various “ee” or “de” Values. In someembodiments, the compound of formula (I) (e.g., as described herein) hasan enantiomeric purity of at least 60% ee (e.g., 60%, 65%, 70%, 75%,80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%ee, or any value between those enumerated values). In some embodiments,the compound of formula (I) (e.g., as described herein) has anenantiomeric purity of greater than 99.9% ee, extending up to 100% ee.In some embodiments, the compound of formula (I) (e.g., as describedherein) has a diastereomeric purity of at least 60% de (e.g., 60%, 65%,70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%,99.5%, 99.9% de, or any value between those enumerated values). In someembodiments, the compound of formula (I) (e.g., as described herein) hasa diastereomeric purity of greater than 99.9% de.

The term “enantiomeric excess” or “ee” designates how much of oneenantiomer is present compared to the other. For a mixture of R and Senantiomers, the percent enantiomeric excess is defined as |R—S|*100,where R and S are the respective mole or weight fractions of enantiomersin a mixture such that R+S=1. With knowledge of the optical rotation ofa chiral substance, the percent enantiomeric excess is defined as([a]obs/[a]max)*100, where [a]obs is the optical rotation of the mixtureof enantiomers and [a]max is the optical rotation of the pureenantiomer.

The term “diastereomeric excess” or “de” designates how much of onediastereomer is present compared to the other and is defined by analogyto enantiomeric excess. Thus, for a mixture of diastereomers, D1 and D2,the percent diastereomeric excess is defined as |D1−D2|*100, where D1and D2 are the respective mole or weight fractions of diastereomers in amixture such that D1+D2=1.

The determination of diastereomeric and/or enantiomeric excess can beaccomplished using a variety of analytical techniques, including NMRspectroscopy, chiral column chromatography and/or optical polarimetryaccording to routine protocols familiar to to those skilled in the art.

The racemates can be used as such or can be resolved into theirindividual isomers. The resolution can afford stereochemically purecompounds or mixtures enriched in one or more isomers. Methods forseparation of isomers are well known (cf. Allinger N. L. and Eliel E. L.in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) andinclude physical methods such as chromatography using a chiraladsorbent. Individual isomers can be prepared in chiral form from chiralprecursors. Alternatively, individual isomers can be separatedchemically from a mixture by forming diastereomeric salts with a chiralacid, such as the individual enantiomers of 10-camphorsulfonic acid,camphoric acid, alpha-bromocamphoric acid, tartaric acid,diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, andthe like, fractionally crystallizing the salts, and then freeing one orboth of the resolved bases, optionally repeating the process, so asobtain either or both substantially free of the other; i.e., in a formhaving an optical purity of, for example, at least 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99% or 99.5% by weight of the desired stereoisomer.Alternatively, the racemates can be covalently linked to a chiralcompound (auxiliary) to produce diastereomers which can be separated bychromatography or by fractional crystallization after which time thechiral auxiliary is chemically removed to afford the pure enantiomers,as is known to the POSITA.

The term “tautomer” as used herein refers to constitutional isomers ofcompounds generated by rapid movement of an atom in two positions in amolecule. Tautomers readily interconvert into each other, e.g., enolform and ketone form are typical tautomers. For example, some compoundsdisclosed herein can exist in the forms of a, b, c, d, e, f, etc., asshown in the figure below, i.e., compounds in the forms of a, b, c, d,e, f are possible the tautomers of the compound of Formula (I). Thesingle tautomer and the mixture of these tautomers in any ratio are allincluded in the compounds described herein.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound of Formula (I) that is non-toxic,biologically tolerable, or otherwise biologically suitable foradministration to the subject. For examples, see, generally, S. M.Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19,and Handbook of Pharmaceutical Salts, Properties, Selection, and Use,Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.

In addition, if a compound described herein is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid addition salt. Conversely, if the product is a free base, anacid addition salt, particularly a pharmaceutically acceptable acidaddition salt, may be produced by dissolving the free base in a suitablesolvent and treating the solution with an acid, in accordance withconventional procedures for preparing acid addition salts from basecompounds. The POSITA will recognize various synthetic methodologiesthat may be used without undue experimentation to prepare non-toxicpharmaceutically acceptable acid addition salts.

The term “solvates” means solvent addition forms that contain eitherstoichiometric or non-stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thesolid state, thus forming a solvate. If the solvent is water, thesolvate formed is a hydrate, when the solvent is alcohol, the solvateformed is an alcoholate. Hydrates are formed by the combination of oneor more molecules of water with one molecule of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrates, for example, hemihydrates,monohydrate, and dihydrate, as well as variable hydrates.

As used herein, the terms “group”, “radical” and “moiety” are synonymousand are intended to indicate functional groups or fragments of moleculesattachable to other fragments of molecules.

The term “active ingredient” is used to indicate a chemical substancewhich has biological activity. In some embodiments, an “activeingredient” is a chemical substance having pharmaceutical utility. Inthe United States, practical pharmaceutical activity can be establishedby appropriate pre-clinical assays, whether in vitro or in vivo.Pharmaceutical activity sufficient to be accepted by a regulatoryagency, such as FDA in the U.S., is a higher standard than thepre-clinical assay. Such a higher standard of pharmaceutical activity,the success of which cannot generally be reasonably expected from thepre-clinical results, can be established by appropriate and successfulrandomized, double blind, controlled clinical trials in humans.

The terms “treating”, “treat,” or “treatment” of a disease or disorder,in the context of achieving therapeutic benefit, refer to administeringone or more pharmaceutical substances, especially a compound of formula(I) and/or a pharmaceutically acceptable salt thereof described hereinto a subject that has the disease or disorder, or has a symptom of adisease or disorder, or has a predisposition toward a disease ordisorder, with the purpose to cure, heal, alleviate, relieve, alter,remedy, ameliorate, improve, or affect the disease or disorder, thesymptoms of the disease or disorder, or the predisposition toward thedisease or disorder. In some embodiments, the disease or disorder iscancer.

The terms “treating”, “contacting” and “reacting,” in the context of achemical reaction, mean adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately lead to the formation of the indicated and/or thedesired product.

The term “effective amount” as used herein refers to an amount or doseof an IDH mutation inhibiting agent sufficient to generally bring abouta therapeutic benefit in patients in need of treatment for a disease ordisorder induced by IDH mutation. Effective amounts or doses of theactive ingredient of the present disclosure may be ascertained bymethods such as modeling, dose escalation studies or clinical trials,and by taking into consideration factors, e.g., the mode or route ofadministration or drug delivery, the pharmacokinetics of the agent, theseverity and course of the disease or disorder, the subject's previousor ongoing therapy, the subject's health status and response to drugs,and the judgment of the attending physician. In the United States, thedetermination of effective doses is generally difficult to predict frompreclinical trials. In fact, the dose is completely unpredictable andthe dose will develop a new unpredictable dosing regimen after initialuse in a randomized, double-blind, controlled clinical trials.

An exemplary dose is in the range of from about 0.0001 to about 200 mgof active agent per kg of subject's body weight per day, such as fromabout 0.001 to 100 mg/kg/day, or about 0.01 to 35 mg/kg/day, or about0.1 to 10 mg/kg daily in single or divided dosage units (e.g., BID, TID,QID). For a 70-kg human, an illustrative range for a suitable dosageamount is from about 0.05 to about 7 g/day, or about 0.2 to about 5g/day. Once improvement of the patient's disease or disorder hasoccurred, the dose may be adjusted for maintenance treatment. Forexample, the dosage or the frequency of administration, or both, may bereduced as a function of the symptoms, to a level at which the desiredtherapeutic effect is maintained. Of course, if symptoms have beenalleviated to an appropriate level, treatment may cease. Patients may,however, require intermittent treatment on a long-term basis upon anyrecurrence of symptoms.

The term “subject” as used herein means mammals and non-mammals. Mammalsmeans any member of the mammalia class including, but not limited to,humans; non-human primates such as chimpanzees and other apes and monkeyspecies; farm animals such as cattle, horses, sheep, goats, and swine;domestic animals such as rabbits, dogs, and cats; laboratory animalsincluding rodents, such as rats, mice, and guinea pigs; and the like.Examples of non-mammals include, but are not limited to, birds, and thelike. The term “subject” does not denote a particular age or sex. Insome embodiments, the subject is a human.

In general, the term “about” is used herein to modify a numerical valueabove and below the stated value by a variance of 20%.

Technical and scientific terms used herein and not specifically definedhave the meaning commonly understood by the POSITA to which the presentdisclosure pertains.

Provided is a compound of formula (I):

and/or a pharmaceutically acceptable salt thereof, and/or solvates,racemic mixtures, enantiomers, diasteromers, and tautomers thereof,wherein

A is chosen from

wherein, R₇ is chosen from H, halo, —CN, —OH, or —NH₂; R₈ is chosen fromhalo, —CN, —OH, or —NH₂; q is 1 or 2;

R₁ is chosen from H, —OH, halo, C₁₋₆ alkyl, C₁₋₆ alkoxyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)₂, oxo, or C₃₋₈ cycloalkyl;

each of R₂ is independently chosen from H, deuterium, halo, —OH, —NH₂,—CN, —SH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, oxo, —OR₅, —OCOR₅, —NHR₅, —N(R₅)(C₁₋₄ alkyl), —COR₅,—NHCOR₅, or 3-8 membered heterocyclyl; in which each of said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl or 3-8 membered heterocyclylis optionally substituted with one or more groups chosen from deuterium,halo, —CN, —OH, —SH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, or C₁₋₆alkoxyl; or two R₂, which attach to the same carbon atom, together withthe carbon atom they are attached to form a 3-5 membered cycloalkylwhich is optionally substituted with one or more halo or deuterium;

R₃, R_(3′), R₄ and R_(4′) are independently chosen from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, 3-12 memberedheterocyclyl, phenyl, 5-12 membered heteroaryl, —C(O)R₅, —OR₅, or —NHR₅,in which each of said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂cycloalkyl, 3-12 membered heterocyclyl, phenyl, or 5-12 memberedheteroaryl is optionally substituted with one or more R₆; wherein R₃,R_(3′), R₄ and R_(4′) are not H simultaneously; provided that when oneof R₃ and R₄ is optionally substituted phenyl or optionally substituted5-6 membered heteroaryl, the other one is —OR₅ or —NHR₅;

or R₃ and R_(3′) are independently chosen from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, 3-12 membered heterocyclyl,phenyl, 5-12 membered heteroaryl, —C(O)R₅, —OR₅, or —NHR₅, in which eachof said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, 3-12membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionallysubstituted with one or more R₆; R₄ and R_(4′) together with the N atomthey are attached to form a 3-8 membered heterocyclic ring optionallysubstituted by one or more R₆;

R₅ is chosen from C₁₋₆ alkyl or C₃₋₈ cycloalkyl, each of which isoptionally substituted with one or more groups independently chosen fromhalo, —CN, —OH, —SH, —NH₂, or C₁₋₆ alkoxyl;

each of R₆ is independently chosen from deuterium, halo, —CN, —OH, —SH,—NH₂, C₁₋₆ alkoxyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, 3-8membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, in which eachof said C₁₋₆ alkoxyl, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, 3-8 memberedheterocyclyl, phenyl, or 5-6 membered heteroaryl is optionallysubstituted with one or more groups independently chosen from halo, —CN,—OH, —SH, —NH₂, C₁₋₆ alkoxyl, C₁₋₆ alkynyl, or C₁₋₆ alkyl;

m is 0, 1, 2, 3, 4, 5, or 6;

n is 0, 1, or 2.

In some embodiments of the compound of formula (I), R₁ is chosen from H,—OH or halo.

In some embodiments of the compound of formula (I), R₁ is chosen from—OH or halo.

In some embodiments of the compound of formula (I), R₁ is —OH.

In some embodiments of the compound of formula (I), R₁ is halo chosenfrom F, Cl, or Br. In some embodiments of the compound of formula (I),R₁ is F.

In some embodiments of the compound of formula (I), the two R₂, whichattach to the same carbon atom, together with the carbon atom they areattached to form a 3-5 membered cycloalkyl optionally substituted by oneor more F.

In some embodiments of the compound of formula (I), the two R₂, whichattach to the same carbon atom, together with the carbon atom they areattached to form a cyclopropyl.

In some embodiments of the compound of formula (I), each of R₂ isindependently chosen from H, deuterium, halo, —OH, —NH₂, —CN, —SH, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, oxo,—OR₅, —OCOR₅, —NHR₅, —N(R₅)(C₁₋₄ alkyl), —NHCOR₅, or 3-8 memberedheterocyclyl.

In some embodiments of the compound of formula (I), each of R₂ isindependently chosen from H, deuterium, halo, —OH, —NH₂, —CN, C₁₋₆alkyl, C₁₋₆ haloalkyl, oxo, —OR₅, —NHR₅, or —N(R₅)(C₁₋₄ alkyl).

In some embodiments of the compound of formula (I), each of R₂ isindependently chosen from H, deuterium, halo, C₁₋₆ alkyl, or C₁₋₆haloalkyl.

In some embodiments of the compound of formula (I), each of R₂ isindependently chosen from halo, such as F, Cl, or Br.

In some embodiments of the compound of formula (I), R₂ is F.

In some embodiments of the compound of formula (I), m is 0, 1, 2, 3, or4.

In some embodiments of the compound of formula (I), m is 0, 1, or 2.

In some embodiments of the compound of formula (I), m is 1. In someembodiments of the compound of formula (I), m is 2. In some embodimentsof the compound of formula (I), m is 3. In some embodiments of thecompound of formula (I), m is 4.

In some embodiments of the compound of formula (I), R₃ and R₄ areindependently chosen from C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, 3-12 memberedheterocyclyl, phenyl, 5-12 membered heteroaryl, —C(O)R₅, —OR₅, or —NHR₅,in which each of said C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, 3-12 memberedheterocyclyl, phenyl, or 5-12 membered heteroaryl is optionallysubstituted with one or more R₆; R_(3′) and R_(4′) are independentlychosen from H or C₁₋₆ alkyl.

In some embodiments of the compound of formula (I), R_(3′) and R_(4′)are both H.

In some embodiments of the compound of formula (I), R₃ and R₄ areindependently chosen from C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, or 3-12 memberedheterocyclyl, each of which is optionally substituted with one or moreR₆; R_(3′) and R_(4′) are both H.

In some embodiments of the compound of formula (I), R₃ and R₄ areindependently chosen from C₁₋₆ alkyl substituted with one ore more halo,5-12 membered heteroaryl substituted with C₁₋₆ haloalkyl, or —OR₅;R_(3′) and R_(4′) are both H.

In some embodiments of the compound of formula (I), R₃ and R₄ areindependently chosen from C₁₋₆ alkyl optionally substituted with one ormore halo; R_(3′) and R_(4′) are both H.

In some embodiments of the compound of formula (I), R₃ is 5-12 memberedheteroaryl substituted with C₁₋₆ haloalkyl, R₄ is C₁₋₆ alkoxyl; R_(3′)and R_(4′) are both H.

In some embodiments of the compound of formula (I), R₃ is 5-7 heteroarylsubstituted with CF₃, R₄ is C₁₋₆ alkoxyl; R_(3′) and R_(4′) are both H.

In some embodiments of the compound of formula (I), R₃ is chosen from H,C₁₋₆ alkyl optionally substituted by C₁₋₆ haloalkyl, or 5-12 memberedheteroaryl optionally substituted by C₁₋₆ haloalkyl; R_(3′) is H; R₄ andR_(4′) together with the N atom they are attached to form a 3-8 memberedheterocyclic ring optionally substituted by one or more groups chosenfrom halo, —OH, or C₁₋₆ haloalkyl.

In some embodiments of the compound of formula (I), R₅ is C₁₋₆ alkyl orC₃₋₈ cycloalkyl.

In some embodiments of the compound of formula (I), R₅ is C₁₋₆ alkyloptionally substituted with one or more halo.

In some embodiments of the compound of formula (I), each of R₆ isindependently chosen from deuterium, halo, —CN, —OH, —NH₂, C₁₋₆ alkoxyl,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, in which each of said C₁₋₆ alkoxyl,C₁₋₆ alkyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6membered heteroaryl is optionally substituted with one or more halo.

In some embodiments of the compound of formula (I), each of R₆ isindependently chosen from deuterium, halo, —OH, C₁₋₆ alkoxyl, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl.

In some embodiments of the compound of formula (I), each of R₆ isindependently chosen from deuterium, halo, —CN, —OH, —NH₂, C₁₋₆ alkoxyl,C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C₃₋₈ cycloalkyl.

In some embodiments of the compound of formula (I), each of R₆ isindependently chosen from deuterium, halo, or C₁₋₆ haloalkyl.

In some embodiments of the compound of formula (I), n is 1.

In some embodiments of the compound of formula (I), R₇ and R₈ areindependently chosen from halo or —CN.

In some embodiments of the compound of formula (I), R₇ and R₈ areindependently chosen from F or —CN.

In some embodiments of the compound of formula (I), the compound offormula (I) is chosen from

wherein X is halo; R₁, R₂, R₃, R_(3′), R₄, R_(4′), m and n are asdefined in the compound of formula (I).

In some embodiments of the compound of formula (I), formula (I) isformula (I-1), wherein R₁, R₂, R₃, R_(3′), R₄, R_(4′), m and n are asdefined in the compound of formula (I),

In some embodiments of the compound of formula (I), formula (I) isformula (I-1a), wherein R₂, R₃, R_(3′), R₄, R_(4′), m and n are asdefined in the compound of formula (I),

In some embodiments of the compound of formula (I), formula (I) isformula (I-1b), wherein R₂, R₃, R_(3′), R₄, R_(4′), m and n are asdefined in the compound of formula (I),

In some embodiments of the compound of formula (I), formula (I) isformula (II), wherein R₁, R₂, R₃, R_(3′), R₄, R_(4′), n and A are asdefined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is0, 1, or 2,

In some embodiments of the compound of formula (II), X is F.

In some embodiments of the compound of formula (II), R₁ is F.

In some embodiments of the compound of formula (II), R₁ is —OH.

In some embodiments of the compound of formula (II), p is 0.

In some embodiments of the compound of formula (II), p is 1.

In some embodiments of the compound of formula (II), p is 2.

In some embodiments of the compound of formula (I), formula (II) ischosen from

wherein R₁, R₂, R₃, R_(3′), R₄, R_(4′), m and n are as defined in thecompound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2.

In some embodiments of the compound of formula (I), formula (II) isformula (II-1), wherein R₁, R₂, R₃, R_(3′), R₄, R_(4′), m and n are asdefined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is0, 1, or 2,

In some embodiments of the compound of formula (I), formula (II) isformula (II-1a), wherein R₂, R₃, R_(3′), R₄, R_(4′), m and n are asdefined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is0, 1, or 2,

In some embodiments of the compound of formula (I), formula (II) isformula (II-1b), wherein R₂, R₃, R_(3′), R₄, R_(4′), m and n are asdefined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is0, 1, or 2,

In some embodiments of the compound of formula (II-1)-formula (II-5), Xis F.

In some embodiments of the compound of formula (II-1)-formula (II-5), R₁is F.

In some embodiments of the compound of formula (II-1)-formula (II-5), R₁is —OH.

In some embodiments of the compound of formula (II-1)-formula (II-5), pis 0.

In some embodiments of the compound of formula (II-1)-formula (II-5), pis 1.

In some embodiments of the compound of formula (II-1)-formula (II-5), pis 2.

In some embodiments of the compound of formula (I), formula (I) isformula (III), wherein R₁, R₂, R₃, R_(3′), R₄, R_(4′), n and A are asdefined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is0, 1, or 2; v is 0, 1, or 2,

In some embodiments of the compound of formula (III), X is F.

In some embodiments of the compound of formula (III), R₁ is F.

In some embodiments of the compound of formula (III), R₁ is —OH.

In some embodiments of the compound of formula (III), p is 0.

In some embodiments of the compound of formula (III), p is 1.

In some embodiments of the compound of formula (III), p is 2.

In some embodiments of the compound of formula (III), v is 0.

In some embodiments of the compound of formula (III), v is 1.

In some embodiments of the compound of formula (III), v is 2.

In some embodiments of the compound of formula (I), formula (III) ischosen from

wherein R₁, R₂, R₃, R_(3′), R₄, R_(4′), m and n are as defined in thecompound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2; vis 0, 1, or 2.

In some embodiments of the compound of formula (I), formula (III) isformula (III-1), wherein R₁, R₂, R₃, R_(3′), R₄, R_(4′), m and n are asdefined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is0, 1, or 2; v is 0, 1, or 2,

In some embodiments of the compound of formula (III-1)-formula (III-5),X is F.

In some embodiments of the compound of formula (III-1)-formula (III-5),R₁ is F.

In some embodiments of the compound of formula (III-1)-formula (III-5),R₁ is —OH.

In some embodiments of the compound of formula (III-1)-formula (III-5),p is 0.

In some embodiments of the compound of formula (III-1)-formula (III-5),p is 1.

In some embodiments of the compound of formula (III-1)-formula (III-5),p is 2.

In some embodiments of the compound of formula (III-1)-formula (III-5),v is 0.

In some embodiments of the compound of formula (III-1)-formula (III-5),v is 1.

In some embodiments of the compound of formula (III-1)-formula (III-5),v is 2.

Also provided is a compound chosen from Compounds 1-87, 89-184, 186-301,as numbered in the experimental section, and/or a pharmaceuticallyacceptable salt thereof.

In another aspect, provided is a pharmaceutical composition, comprisinga compound of formula (I) (e.g., any of the compounds described herein)and/or a pharmaceutically acceptable salt thereof, and optionallycomprising at least one pharmaceutically acceptable excipient (e.g., apharmaceutically acceptable carrier).

In another aspect, provided is a method of treating a disease induced byIDH mutation in a subject, comprising administering to the subject inneed thereof an amount of a compound of formula (I) (e.g., any of thecompounds described herein) and/or a pharmaceutically acceptable saltthereof effective to inhibit the increase of α-hydroxyglutaric acid(2HG) induced by IDH mutation in said subject.

In another aspect, provided is a method of treating a disease induced byIDH mutation in a subject, comprising administering to the subject inneed thereof an amount of a pharmaceutical composition comprising acompound of formula (I) (e.g., any of the compounds described herein)and/or a pharmaceutically acceptable salt thereof and at least onepharmaceutically acceptable excipient (e.g., a pharmaceuticallyacceptable carrier) effective to inhibit the increase ofα-hydroxyglutaric acid (2HG) induced by IDH mutation in said subject.

In another aspect, provided is a use of a compound of formula (I) (e.g.,any of the compounds described herein) and/or a pharmaceuticallyacceptable salt thereof described herein for treating a disease inducedby IDH mutation by inhibiting the increase of α-hydroxyglutaric acid(2HG) induced by IDH mutation in a subject.

In another aspect, provided is a use of a compound of formula (I) (e.g.,any of the compounds described herein) and/or a pharmaceuticallyacceptable salt thereof described herein in the manufacture of amedicament for treating a disease induced by IDH mutation.

In some embodiments, the IDH mutation is IDH1 gene mutation.

In some embodiments, the IDH mutation is IDH2 gene mutation.

In some embodiments, the IDH mutation is IDH1-R132H or IDH2-R140Q genemutation.

In some embodiments, the disease induced by IDH mutation is cancer.

In some embodiments, the cancer is chosen from solid cancer,neurogliocytoma, or hematological malignant tumor, such as leukemia,lymphoma, or myeloma.

In some embodiments, the cancer is chosen from acute myeloid leukemia(AML), acute promyelocytic leukemia (APL), glioblastoma (GBM),myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN),cholangiocarcinoma, such as intrahepatic cholangiocarcinoma (IHCC),chondrosarcoma, giant cell tumor, intestinal cancer, melanoma, lungcancer, or non-Hodgkin's lymphoma (NHL).

In another aspect, provided is a compound of formula (IV) and/or a saltthereof, and/or racemic mixtures or enantiomers thereof, which can beused in the manufacture of compounds of formula (I) (e.g., any of thecompounds described herein),

wherein, R₁, R₂, m and n are as defined in the compound of formula (I);R_(a) is chosen from halo, —OS(O)₂CF₃, —B(OH)₂, —B(OC₁₋₆ alkyl)₂,

R_(b) is H or C₁₋₆ alkyl.

In some embodiments of the compound of formula (IV), R_(a) is chosenfrom —B(OH)₂, —B(OC₁₋₆ alkyl)₂,

R_(b) is H or C₁₋₆ alkyl.

In some embodiments of the compound of formula (IV), R_(a) is chosenfrom —B(OH)₂, —B(OCH₃)₂, —B[OCH(CH₃)₂]₂,

In some embodiments of the compound of formula (IV), formula (IV) isformula (IV-1), wherein m is 0, 1, or 2;

In some embodiments of the compound of formula (IV), formula (IV) isformula (IV-2), wherein X is halo; m is 0, 1, or 2;

In some embodiments of the compound of formula (IV), formula (IV) isformula (IV-3), wherein X is halo; p is 0, 1, or 2; m is 0, 1, or 2;

In some embodiments of the compound of formula (IV), R₁ is —OH or oxo.

In some embodiments of the compound of formula (IV), X is F.

In some embodiments of the compound of formula (IV), p is 0.

In some embodiments of the compound of formula (IV), p is 1.

In some embodiments of the compound of formula (IV), p is 2.

In some embodiments of the compound of formula (IV), the compound offormula (IV) is chosen from

In some embodiments of the compound of formula (IV), the compound offormula (IV) is chosen from

General Synthetic Methods for Disclosed Embodiments

The compound of formula (I) and/or a pharmaceutically acceptable saltthereof described herein can be synthesized from commercially availablestarting material by methods well known in the art, taken together withthe disclosure in this patent application. The drawings 1-6 illustrategeneral methods for preparation of the compounds described herein.

As shown in FIG. 1, substitution reaction of2,4,6-trichloro-1,3,5-triazine with an amine substituted with R₃ andR_(3′) provides compound of formula 1-1. Substitution reaction of thecompound of formula 1-1 with an amine substituted with R₄ and R_(4′)provides compound of formula 1-2. Suzuki coupling reaction of compoundof formula 1-2 with an intermediate represented by formula (IV) underthe catalysis of a suitable palladium reagent gives a compound offormula (I-1) as described herein, wherein R₁, R₂, R₃, R_(3′), R₄,R_(4′), Ra, m, and n are as defined herein. The Pd-catalyzed C—Ccoupling reaction can be carried out under suitable conditions, and thesolvent used can be selected from polar solvents such as 1,4-dioxane,DMF, THF, a mixture of 1,4-dioxane and water and the like, the base usedcan be selected from Cs₂CO₃, Na₂CO₃, K₃PO₄ and the like, and thecatalyst used can be selected from Pd(dppf)Cl₂CH₂Cl₂, Pd(PPh₃)₄,Pd(OAc)₂ and the like.

As shown in Scheme 2, Suzuki coupling reaction of compound of formula1-1 with an intermediate represented by formula (IV) under the catalysisof a suitable palladium reagent affords compound of formula 2-1.Substitution reaction of compound of formula 2-1 with an aminesubstituted with R₄ and R_(4′) gives a compound of formula (I-1) asdescribed herein, wherein R₁, R₂, R₃, R_(3′), R₄, R_(4′), Ra, m, and nare as defined herein.

As shown in Scheme 3, Suzuki coupling reaction of compound of formula1-2 with an intermediate represented by formula (IV-1) under thecatalysis of a suitable palladium reagent provides compound of formula3-1. The Pd-catalyzed C—C coupling reaction can be carried out undersuitable conditions, and the solvent used can be selected from polarsolvents such as 1,4-dioxane, DMF, THF, a mixture of 1,4-dioxane andwater and the like, the base used can be selected from Cs₂CO₃, Na₂CO₃,K₃PO₄ and the like, and the catalyst used can be selected fromPd(dppf)Cl₂CH₂Cl₂, Pd(PPh₃)₄, Pd(OAc)₂ and the like. Reduction ofcompound of formula 3-1 provides compound of formula (I-1a) as describedherein.

As shown in Scheme 4, Suzuki coupling reaction of compound of formula1-1 with an intermediate represented by formula (IV-1) under thecatalysis of a suitable palladium reagent affords compound of formula4-1. Reduction of Compound of formula 4-1 provides compound of formula4-2. Substitution reaction of compound of formula 4-2 with an aminesubstituted with R₄ and R_(4′) gives a compound of formula (I-1a) asdescribed herein.

As shown in Scheme 5, Suzuki coupling reaction of compound of formula1-2 with an intermediate represented by formula (IV-2) under thecatalysis of a suitable palladium reagent provides compound of formula5-1. Halogenation of compound of formula 5-1 using a halogenatingreagent such as NFSI and the like, in presence of a base such as LiHMDS,KHMDS, LDA and the like, and in suitable polar solvents such as THF, DCMand the like, results in compound of formula 5-2. Reduction of compoundof formula 5-2 provides compound of formula (II-1a) as described herein.

As shown in Scheme 6, compound of formula 3-1 reacts with a deuteratingreagent such as NaBD₄, deuterated borane and the like gives a compoundof formula (I-1b) as described herein.

The substituents of the compounds thus obtained can be further modifiedto provide other desired compounds. Synthetic chemistry transformationsare described, for example, in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieserand Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994);and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis,John Wiley and Sons (1995) and subsequent editions thereof.

Before use, the compound of formula (I) and/or a pharmaceuticallyacceptable salt thereof described herein can be purified by columnchromatography, high performance liquid chromatography, crystallizationor other suitable methods.

Pharmaceutical Compositions and Practical Utility

The compound of formula (I) (e.g., any of those described herein) and/ora pharmaceutically acceptable salt thereof described herein is used,alone or in combination with one or more additional active ingredients,to formulate pharmaceutical compositions. A pharmaceutical compositioncomprises: (a) an effective amount of a compound of formula (I) and/or apharmaceutically acceptable salt thereof described herein; and (b) apharmaceutically acceptable excipient (e.g., a pharmaceuticallyacceptable carrier).

A pharmaceutically acceptable carrier refers to a carrier that iscompatible with active ingredients of the composition (and in someembodiments, capable of stabilizing the active ingredients) and notdeleterious to the subject to be treated. For example, solubilizingagents, such as cyclodextrins (which form specific, more solublecomplexes with the compound of formula (I) and/or a pharmaceuticallyacceptable salt thereof described herein), can be utilized aspharmaceutical excipients for delivery of the active ingredients.Examples of other carriers include colloidal silicon dioxide, magnesiumstearate, cellulose, sodium lauryl sulfate, and pigments such as D&CYellow #10. Suitable pharmaceutically acceptable carriers are disclosedin Remington's Pharmaceutical Sciences, A. Osol, a standard referencetext in the art.

A pharmaceutical composition comprising a compound of formula (I) (e.g.,any of those described herein) and/or a pharmaceutically acceptable saltthereof described herein can be administered in various known manners,such as orally, topically, rectally, parenterally, by inhalation spray,or via an implanted reservoir. The term “parenteral” as used hereinincludes subcutaneous, intracutaneous, intravenous, intramuscular,intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal,intralesional and intracranial injection or infusion techniques.

A pharmaceutical composition described herein can be prepared in theform of tablet, capsule, sachet, dragee, powder, granule, lozenge,powder for reconstitution, liquid preparation, or suppository. In someembodiments, a pharmaceutical composition comprising a compound offormula (I) and/or a pharmaceutically acceptable salt thereof isformulated for intravenous infusion, topical administration, or oraladministration.

An oral composition can be any orally acceptable dosage form including,but not limited to, tablets, capsules, emulsions, and aqueoussuspensions, dispersions and solutions. Commonly used carriers fortablets include lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added to tablets. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions or emulsions areadministered orally, the active ingredient can be suspended or dissolvedin an oily phase combined with emulsifying or suspending agents. Ifdesired, certain sweetening, flavoring, or coloring agents can be added.

In some embodiments, the compound of formula (I) and/or apharmaceutically acceptable salt thereof can be present in an amount of1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250,300, 400 and 500 mg in a tablet. In some embodiments, the compound offormula (I) and/or a pharmaceutically acceptable salt thereof can bepresent in an amount of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95,100, 125, 150, 200, 250, 300, 400 and 500 mg in a capsule.

A sterile injectable composition (e.g., aqueous or oleaginoussuspension) can be formulated according to techniques known in the artusing suitable dispersing or wetting agents (such as, for example, Tween80) and suspending agents. The sterile injectable Intermediate can alsobe a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the pharmaceutically acceptable vehicles andsolvents that can be employed are mannitol, water, Ringer's solution andisotonic sodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium (e.g.,synthetic mono- or di-glycerides). Fatty acids, such as oleic acid andits glyceride derivatives are useful in the Intermediate of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions can also contain a long-chain alcohol diluentor dispersant, or carboxymethyl cellulose or similar dispersing agents.

An inhalation composition can be prepared according to techniques wellknown in the art of pharmaceutical formulation and can be prepared assolutions in saline, employing benzyl alcohol or other suitablepreservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

A topical composition can be formulated in form of oil, cream, lotion,ointment, and the like. Suitable carriers for the composition includevegetable or mineral oils, white petrolatum (white soft paraffin),branched chain fats or oils, animal fats and high molecular weightalcohols (greater than C12). In some embodiments, the pharmaceuticallyacceptable carrier is one in which the active ingredient is soluble.Emulsifiers, stabilizers, humectants and antioxidants may also beincluded as well as agents imparting color or fragrance, if desired.Additionally, transdermal penetration enhancers may be employed in thosetopical formulations. Examples of such enhancers can be found in U.S.Pat. Nos. 3,989,816 and 4,444,762.

Creams may be formulated from a mixture of mineral oil, self-emulsifyingbeeswax and water in which mixture the active ingredient, dissolved in asmall amount of an oil, such as almond oil, is admixed. An example ofsuch a cream is one which includes, by weight, about 40 parts water,about 20 parts beeswax, about 40 parts mineral oil and about 1 partalmond oil. Ointments may be formulated by mixing a solution of theactive ingredient in a vegetable oil, such as almond oil, with warm softparaffin and allowing the mixture to cool. An example of such anointment is one which includes about 30% by weight almond oil and about70% by weight white soft paraffin.

Suitable in vitro assays can be used to evaluate the practical utilityof the compound of formula (I) and/or a pharmaceutically acceptable saltthereof described herein, in inhibiting the IDH mutation. The compoundof formula (I) and/or a pharmaceutically acceptable salt thereofdescribed herein can further be examined for additional practicalutility in treating cancer by in vivo assays. For example, the compoundof formula (I) and/or a pharmaceutically acceptable salt thereofdescribed herein can be administered to an animal (e.g., a mouse model)having cancer and its therapeutic effects can be accessed. If thepre-clinical results are successful, the dosage range and administrationroute for animals, such as humans, can be projected.

The compound of formula (I) and/or a pharmaceutically acceptable saltthereof described herein can be shown to have sufficient pre-clinicalpractical utility to merit clinical trials hoped to demonstrate abeneficial therapeutic or prophylactic effect, for example, in subjectswith cancer.

As used herein, the term “cancer” refers to a cellular disordercharacterized by uncontrolled or disregulated cell proliferation,decreased cellular differentiation, inappropriate ability to invadesurrounding tissue, and/or ability to establish new growth at ectopicsites. The term “cancer” includes, but is not limited to, solid tumorsand hematologic malignancies. The term “cancer” encompasses diseases ofskin, tissues, organs, bone, cartilage, blood, and vessels. The term“cancer” further encompasses primary and metastatic cancers.

Non-limiting examples of solid tumors include pancreatic cancer; bladdercancer; colorectal cancer; breast cancer, including metastatic breastcancer; prostate cancer, including androgen-dependent andandrogen-independent prostate cancer; renal cancer, including, e.g.,metastatic renal cell carcinoma; hepatocellular cancer; lung cancer,including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolarcarcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer,including, e.g., progressive epithelial or primary peritoneal cancer;cervical cancer; gastric cancer; esophageal cancer; head and neckcancer, including, e.g., squamous cell carcinoma of the head and neck;skin cancer, including e.g., malignant melanoma; neuroendocrine cancer,including metastatic neuroendocrine tumors; brain tumors, including,e.g., glioma, anaplastic oligodendroglioma, adult glioblastomamultiforme, and adult anaplastic astrocytoma; bone cancer; soft tissuesarcoma; and thyroid carcinoma.

Non-limiting examples of hematologic malignancies include acute myeloidleukemia (AML); chronic myelogenous leukemia (CML), includingaccelerated CML and CML blast phase (CML-BP); acute lymphoblasticleukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's lymphoma;non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantlecell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM);Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS),including refractory anemia (RA), refractory anemia with ringedsiderblasts (RARS), refractory anemia with excess blasts (RAEB), andRAEB in transformation (RAEB-T); and myeloproliferative syndromes.

In some embodiment, exemplary hematologic malignancies include leukemia,such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML),chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia(CML); multiple myeloma (MM); and lymphoma, such as Hodgkin's lymphoma,non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicularlymphoma, B-cell lymphoma, T-cell lymphoma, and diffuse large B-celllymphoma (DLBCL).

The compound of formula (I) and/or a pharmaceutically acceptable saltdescribed herein can be used to achieve a beneficial therapeutic orprophylactic effect, for example, in subjects with cancer.

In addition, the compound of formula (I) (e.g., any of those describedherein) and/or a pharmaceutically acceptable salt thereof describedherein may be used in combination with additional active ingredients inthe treatment of cancer. The additional active ingredients may becoadministered separately with the compound of formula (I) and/or apharmaceutically acceptable salt thereof described herein or includedwith such an ingredient in a pharmaceutical composition according to thedisclosure, such as a fixed-dose combination drug product. In anexemplary embodiment, additional active ingredients are those that areknown or discovered to be effective in the treatment of diseases inducedby IDH mutation, such as another mutant IDH inhibitor or a compoundactive against another target associated with the particular disease.The combination may serve to increase efficacy (e.g., by including inthe combination a compound potentiating the potency or effectiveness ofthe compound of formula (I) and/or a pharmaceutically acceptable saltthereof described herein), decrease one or more side effects, ordecrease the required dose of the compound of formula (I) and/or apharmaceutically acceptable salt thereof described herein.

In some embodiments, the compound of formula (I) (e.g., any of thosedescribed herein) and/or a pharmaceutically acceptable salt thereofdescribed herein is administered in conjunction with an anti-neoplasticagent. As used herein, the term “anti-neoplastic agent” refers to anyagent that is administered to a subject with cancer for purposes oftreating the cancer. Nonlimiting examples anti-neoplastic agentsinclude: radiotherapy; immunotherapy; DNA damaging chemotherapeuticagents; and chemotherapeutic agents that disrupt cell replication.

Non-limiting examples of DNA damaging chemotherapeutic agents includetopoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecinand analogs or metabolites thereof, and doxorubicin); topoisomerase IIinhibitors (e.g., etoposide, teniposide, mitoxantrone, idarubicin, anddaunorubicin); alkylating agents (e.g., melphalan, chlorambucil,busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine,streptozocin, decarbazine, methotrexate, mitomycin C, andcyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, andcarboplatin); DNA intercalators and free radical generators such asbleomycin; and nucleoside mimetics (e.g., 5-fluorouracil, capecitibine,gemcitabine, fludarabine, cytarabine, azacitidine (VIDAZA®);mercaptopurine, thioguanine, pentostatin, and hydroxyurea).

Chemotherapeutic agents that disrupt cell replication include:paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, andrelated analogs; thalidomide and related analogs (e.g., CC-5013 andCC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylateand gefitinib); proteasome inhibitors (e.g., bortezomib); NF-kappa Binhibitors, including inhibitors of I kappa B kinase; antibodies whichbind to proteins overexpressed in cancers and thereby downregulate cellreplication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab);and other inhibitors of proteins or enzymes known to be upregulated,over-expressed or activated in cancers, the inhibition of whichdownregulates cell replication.

EXAMPLES

The examples below are intended to be exemplary and should not beconsidered to be limiting in any way. Efforts have been made to ensureaccuracy with respect to numbers used (for example, amounts,temperature, etc.) but some experimental errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in degrees Centigrade, and pressure is at or nearatmospheric. All MS data was determined by agilent 6120 or agilent 1100.All NMR data were generated using a Varian 400-MR machine. All reagents,except intermediates, used in this invention are commercially available.All compound names except the reagents were generated by Chemdraw 12.0.

If there is any atom with empty valence(s) in any one of the structuresdisclosed herein, the empty valence(s) is(are) the hydrogen atom(s)which is(are) omitted for convenience purpose.

In the present application, in the case of inconsistency of thestructure and name of a compound, when the two of which are both givenfor the compound, it is subject to the structure of the compound, unlessthe context shows that the structure of the compound is incorrect andthe name is correct.

In the following examples, the abbreviations below are used:

-   -   AcOK potassium acetate    -   BAST bis(2-methoxyethyl)aminosulfur trifluoride    -   BINAP (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene    -   t-BuONa sodium tert-butoxide    -   (n-Bu₃Sn)₂ 1,1,1,2,2,2-hexabutyldistannane    -   (S)—CBS        (S)-3,3-diphenyl-1-methylpyrrolidino[1,2-c]-1,3,2-oxazaborole    -   CD₃OD methanol-d₄    -   DAST diethylaminosulphur trifluoride    -   DCM dichloromethane    -   DIEA N,N-diisopropylethylamine    -   DMF N,N-dimethylformamide    -   DMSO-d₆ dimethyl sulfoxide-d₆    -   EA/EtOAc ethyl acetate    -   Et₃N triethylamine    -   EtOH ethanol    -   Et₂Zn diethyl zinc    -   G gram    -   HC(OMe)₃ trimethyl orthoformate    -   L litre    -   LiHMDS lithium bis(trimethylsilyl)amide    -   M mol/L    -   MeOH methanol    -   MeCN acetonitrile    -   Mg milligram    -   mL millilitre    -   Mmol millimole    -   Mol mole    -   NaBH(OAc)₃ sodium triacetoxyborohydride    -   NaOMe sodium methoxide    -   NaOEt sodium ethoxide    -   NCS N-chlorosuccinimide    -   NFSI N-fluorobenzenesulfonimide    -   PdCl₂(PPh₃)₂ bis(triphenylphosphine)palladium(II) dichloride    -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)    -   Pd(dppf)Cl₂        [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)    -   Pd(dppf)Cl₂.CH₂Cl₂        [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)        dichloromethane complex    -   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)    -   PE petroleum ether    -   Selectfluor®        1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane        bis(tetrafluoroborate),    -   TBAF tetrabutylammonium fluoride    -   TBSOTf tert-butyldimethylsilyltrifluoromethanesulfonate    -   TFA trifluoroacetic acid    -   Tf₂O trifluoromethanesulfonic anhydride    -   THF tetrahydrofuran    -   TsOH.H₂O 4-methylbenzenesulfonic acid monohydrate

Example 1 Preparation of Intermediates Intermediate I-13-(4-Chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-oland Intermediate I-61(*)3-(4-Chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-ol

(A) 2-Fluoro-3-hydroxycyclohex-2-en-1-one (A1)

A mixture of cyclohexane-1,3-dione (30 g, 268 mmol) and Selectfluor®(94.8 g, 268 mmol) in MeCN (1.2 L) was stirred at 70° C. for 96 hoursunder nitrogen atmosphere. Then, the mixture was concentrated in vacuo.The residue was dissolved in DCM (1.2 L) and filtered. The filtrate wasconcentrated in vacuo and purified by flash column chromatography(eluting with gradient PE/EA=100:0-0:100) to give compound A1 as whitesolid (7.7 g, yield: 22%). MS (m/z): 131.1 [M+H]⁺

(B) 2-Fluoro-3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate (A2)

Under nitrogen atmosphere, compound A1 (208 mg, 1.6 mmol) was dissolvedin DCM and cooled to 0° C. Then, DIEA (415 mg, 3.2 mmol) and Tf₂O (540mg, 1.92 mmol) were added at 0° C. and the mixture was stirred for 2hours at 0° C. under nitrogen atmosphere. After the reaction wascompleted, it was quenched by the addition of water and extracted withDCM. The organic layer was collected, condensed and purified by flashcolumn chromatography (eluting with PE/EA) to give compound A2 as yellowoil (220 mg, yield: 52.5%). MS (m/z): 263.0 [M+H]⁺

(C)(R)-4,6-dichloro-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine(A3)

A solution of 2,4,6-trichloro-1,3,5-triazine (9.1 g, 49.3 mmol) in dryTHF was cooled to 0° C. and (R)-1,1,1-trifluoropropan-2-aminehydrochloride (7.37 g, 49.3 mmol) was added. The reaction mixture wasstirred at room temperature for 16 hours. After reaction was completed,the mixture was adjusted to pH=7 by the addition of saturated NaHCO₃aqueous solution and extracted with EtOAc. The organic layer wascollected, condensed and purified by flash column chromatography(eluting with gradient PE/EA=100:0-0:100) to give compound A3 ascolorless oil (7.8 g, yield: 60.6%). MS (m/z): 260.9[M+H]⁺

(D)(R)-3-(4-chloro-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-one(A4)

Under nitrogen atmosphere, a mixture of compound A2 (4.0 g, 15.3 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.3 g, 16.8mmol), AcOK (3.8 g, 38.3 mmol), Pd(dppf)Cl₂ (0.63 g, 0.77 mmol) in1,4-dioxane (40 mL) was stirred at reflux for 2 hours. Then, thereaction mixture was cooled to room temperature, then was added compoundA3 (4.0 g, 15.3 mmol), Cs₂CO₃ (14.4 g, 38.3 mmol), Pd(PPh₃)₄ (0.89 g,0.77 mmol) and water (8 mL) in sequence. The reaction was stirred at 80°C. for another 2 hours. After the reaction was completed, the mixturewas cooled to room temperature, condensed and purified by flash columnchromatography (eluting with gradient PE/EA=100:0-0:100) to givecompound A4 as white solid (0.8 g, yield: 15.4%). MS (m/z): 339.0[M+H]⁺

(E)3-(4-Chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-ol(I-1

To a flask were added compound A4 (1150 mg, 3.41 mmol), CeCl₃.7H₂O (1269mg, 3.41 mmol) and EtOH (20 mL). The mixture was cooled to 0° C., NaBH₄(130 mg, 3.41 mmol) was added and the mixture was stirred at 0° C. for 2hours. After the reaction was completed, the mixture was quenched by theaddition of saturated NH₄Cl aqueous solution (10 mL) and water (50 mL)and extracted with EtOAc. The organic layer was collected, condensed andpurified by flash column chromatography (eluting with gradientPE/EA=100:0-0:100) to give I-1 as white solid (800 mg, yield: 68.9%). MS(m/z): 341.2 [M+H]⁺

(F)(*)3-(4-Chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-ol(I-61

Under nitrogen atmosphere, to dry THF (5 mL) was added 1 mol/L(S)—CBS/THF solution (2.4 mL, 2.4 mmol) under ice bath cooling ° C.,then 2 mol/L BH₃.Me₂S/THF solution (2.4 mL, 4.8 mmol) was added inone-portion. After stirred for 2 minutes, to the above solution wasadded compound A4 (800 mg, 2.4 mmol) in THF (3 mL) dropwise. Afterstirring under ice bath cooling ° C. for 1 hour, to the reaction mixturewas added MeOH (0.5 mL), EtOAc (10 mL) and water (20 mL). The organiclayer was collected. The aqueous phase was extracted with EtOAc (10 mL).The organic layers were combined, dried over Na₂SO₄, filtered. Thefiltrate was condensed and purified by flash column chromatography(eluting with gradient PE/EA=100:0-0:100) to give Intermediate I-61 aswhite solid (360 mg). MS (m/z): 341.2 [M+H]⁺

The compounds in the below table were prepared according to theprocedure of Intermediate I-1 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by thePOSITA:

MS Intermediate Structure (M + H)⁺ I-22

314.0 I-23

279.1 I-24

265.1 I-25

323.0 I-80

285.0

Intermediate I-2(R)-6-Chloro-N²-isopropyl-N⁴-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

To a sealed tube was added compound A3 (3.5 g, 13.4 mmol),propan-2-amine (872 mg, 14.7 mmol), DIEA (3.5 g, 26.8 mmol) and THF (20mL) in sequence, and the mixture was stirred at 50° C. overnight. Afterthe reaction was completed, the mixture was cooled to room temperature,condensed and purified by flash column chromatography (eluting withPE/EA) to give Intermediate I-2 as white solid (3.8 g, yield: 100%). MS(m/z): 284.0 [M+H]⁺

The compounds in the below table were prepared according to theprocedure of Intermediate I-2 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Intermediate Structure (M + H)⁺ I-7

314.0 I-8

312.0 I-9

332.0 I-11

346.0 I-12

310.0 I-13

298.1 I-14

346.0 I-15

296.0 I-16

282.0 I-17

300.0 I-18

284.0 I-19

270.0 I-20

324.1 I-21

333.0 I-30

332.0 I-31

310.0 I-33

352.2 I-35

298.1 I-36

276.0 I-37

278.0 I-38

290.0 I-39

291.1 I-40

291.1 I-42

285.1 I-49

318.0 I-50

318.0 I-51

321.0 I-54

332.0 I-55

362.1 I-71

284.0 I-72

320.4 I-73

308.1 I-74

296.1 I-75

350.9 I-76

323.9 I-77

296.0 I-78

284.0 I-79

351.0 I-81

321.0 I-82

346.0 I-83

288.0 I-84

318.0 I-85

282.2 I-86

324.0 I-87

333.0 I-89

338.0 I-90

314.1 I-91

314.1 I-101

318.0 I-102

318.1

Intermediate I-36-Chloro-N²,N⁴-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamineCF₃

At 0° C., to a flask were added 1,4-dioxane (50 mL),2,4,6-trichloro-1,3,5-triazine (1.84 g, 10 mmol),(R)-1,1,1-trifluoropropan-2-amine hydrochloride (2.99 g, 20 mmol) andDIEA (5.17 g, 40 mmol). The reaction was heated to 60° C. and stirredfor 4 hours. After the reaction was completed, the mixture was condensedand purified by flash column chromatography (eluting with gradientwater/MeOH=100:0-0:100) to give Intermediate I-3 as yellow solid (2.50g, yield: 74%). MS (m/z): 338.0 [M+H]⁺

The compounds in the below table were prepared according to theprocedure of Intermediate I-3 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Intermediate Structure (M + H)⁺ I-6

254.1 I-10

326.0 I-32

338.0 I-34

230.1 I-106

446.0

Intermediate I-4(R)—N-(4-Chloro-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)isobutyramide

A mixture of 4,6-dichloro-1,3,5-triazin-2-amine (1 g, 6.06 mmol) inisobutyryl chloride (5 mL) was stirred at 100° C. for 2 hours. After thereaction was completed, the mixture was cooled to room temperature andconcentrated to dryness in vacuo to affordN-(4,6-dichloro-1,3,5-triazin-2-yl)isobutyramide as yellow solid. Then,to 1,4-dioxane (10 mL) was addedN-(4,6-dichloro-1,3,5-triazin-2-yl)isobutyramide obtained above,(R)-1,1,1-trifluoropropan-2-amine hydrochloride (900 mg, 6.06 mmol) andDIEA (2.34 g, 18.18 mmol). The mixture was heated to reflux and stirredfor 2 hours. After the reaction was completed, the mixture was quenchedby the addition of water, extracted with EtOAc (20 mL). The organiclayer was collected, concentrated under reduced pressure and purified byflash column chromatography (eluting with PE/EA) to give IntermediateI-4 (80 mg). MS (m/z): 312.1 [M+H]⁺

Intermediates I-26 and I-273-(4-Chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-oloptically pure diastereoisomers

Intermediates I-26 and I-27 were obtained by resolution of IntermediateI-25 using chiral HPLC (chiral HMPL conditions: column: AS-H; mobilephase: n-heptane/isopropanol=80:20; flow rate: 0.5 mL/min; detectionwavelength: UV 254 nm). The isomer obtained from the first eluent(RT=1.703 min) was named as I-26, de %=100%, MS (m/z): 400.1 [M+H]⁺. Theisomer obtained from the second eluent (RT=2.067 min) was named as I-27,de %=99.4%, MS (m/z): 400.1 [M+H]⁺).

Intermediate I-416-Chloro-N²-(propan-2-yl-d₇)-N⁴-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

(A)4,6-Dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine(A5)

To a solution of 2,4,6-trichloro-1,3,5-triazine (1.84 g, 10 mmol) and2-(trifluoromethyl)pyridin-4-amine (1.62 g, 10 mmol) in dry THF (20 mL)was added NaHCO₃ (1.68 g, 20 mmol) at 0° C. The mixture was stirred atroom temperature for 16 hours. After reaction was completed, the mixturewas filtered. The filtrate was condensed and purified by flash columnchromatography (eluting with gradient PE/EA=100:0-0:100) to givecompound A5 as white solid (2.68 g, yield: 86%). MS (m/z): 309.9 [M+H]⁺

(B)6-Chloro-N²-(propan-2-yl-d₇)-N⁴-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

To a sealed tube were added compound A5 (465 mg, 1.5 mmol),propan-d₇-2-amine hydrochloride (154 mg, 1.5 mmol), DIEA (388 mg, 3.0mmol) and 1,4-dioxane (20 mL) in sequence. The mixture was heated to 60°C. and stirred for 5 hours. After reaction was completed, the mixturewas cooled to room temperature, condensed and purified by flash columnchromatography (eluting with gradient PE/EA=100:0-0:100) to giveIntermediate I-41 as white solid (485 mg, yield: 95%). MS (m/z): 340.0[M+H]⁺

The compounds in the below table were prepared according to theprocedure of Intermediate I-41 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Intermediate Structure (M + H)⁺ I-43

268.0 I-44

308.0 I-45

304.0 I-53

334.0 I-59

329.0 I-63

363.0 I-66

363.0 I-68

364.0 I-92

321.1 I-93

335.1 I-94

361.1 I-96

329.0 I-97

349.1 I-98

381.1 I-99

385.0 I-100

366.9 I-101

318.0 I-103

428.9 I-104

416.9 I-105

362.1

Intermediate I-462-((4-(Tert-butoxyamino)-6-chloro-1,3,5-triazin-2-yl)amino)isonicotinonitrile

(A) O-(Tert-butyl)-N-(4,6-dichloro-1,3,5-triazin-2-yl)hydroxylamine (A6)

To a solution of 2,4,6-trichloro-1,3,5-triazine (0.92 g, 5 mmol) andO-(tert-butyl)hydroxylamine hydrochloride (0.63 g, 5 mmol) in dry THF(50 mL) was added NaHCO₃ (1.26 g, 15 mmol) at 0° C. The mixture wasstirred at 0° C. for 2 hours. After the reaction was completed, themixture was filtered. The filtrate was condensed and purified by flashcolumn chromatography (eluting with gradient PE/EA=100:0-0:100) to givecompound A6 as colorless oil (0.83 g, yield: 80%). MS (m/z): 237.0[M+H]⁺

(B)2-((4-(Tert-butoxyamino)-6-chloro-1,3,5-triazin-2-yl)amino)isonicotinonitrile

To a sealed tube were sequentially added compound A6 (0.83 g, 4.0 mmol),2-aminoisonicotinonitrile (0.48 g, 4.0 mmol), Pd(dppf)Cl₂ (0.15 g, 0.2mmol), t-BuONa (0.77 g, 8.0 mmol) and 1,4-dioxane (10 mL). The mixturewas heated to 90° C. and stirred for 3 hours. After reaction wascompleted, the mixture was cooled to room temperature, condensed andpurified by flash column chromatography (eluting with gradientPE/EA=100:0-0:100) to give Intermediate I-46 as yellow solid (109 mg,yield: 8%). MS (m/z): 320.0 [M+H]⁺

The compounds in the below table were prepared according to theprocedure of Intermediate I-46 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Intermediate Structure (M + H)⁺ I-47

329.0 I-48

315.0 I-52

305.0 I-56

358.0 I-57

304.1 I-58

295.0 I-60

295.1 I-62

369.0 I-64

385.0 I-65

313.0 I-67

283.0 I-69

304.0 I-70

308.0 I-5

304.0 I-28

309.0 I-29

310.0 I-95

363.9

Intermediate I-882-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one

Under nitrogen atmosphere, to a flask were added compound A2 (80 g, 305mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (80g, 315 mmol), AcOK (74.8 g, 763 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (12.4 g, 15.3mmol) and 1,4-dioxane (1.4 L) in sequence. The mixture was stirred at90° C. for 4 hours, then cooled to room temperature, and filtered. Thefiltrate was condensed and purified by flash column chromatography(eluting with PE/EA=4/1) to give Intermediate I-88 as yellow solid (76g, yield 100%). MS (m/z): 159.0 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ 2.47-2.36 (m, 4H), 1.91-1.82 (m, 2H), 1.22(s, 12H).

Example 2 Synthesis of Compounds 1-87, 89-184, 186-301 Compound 12-Fluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol

(A)(R)-2-fluoro-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one(B1)

Under nitrogen atmosphere, to a flask were added compound A2 (220 mg,0.84 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(234 mg, 0.92 mmol), AcOK (206 mg, 2.10 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (32mg, 0.04 mmol) and 1,4-dioxane (20 mL) in sequence and stirred at refluxfor 16 hours. Then, the mixture was cooled to room temperature, and wasadded Intermediate I-2 (238 mg, 0.84 mmol), Cs₂CO₃ (682 mg, 2.1 mmol),Pd(PPh₃)₄ (46.2 mg, 0.04 mmol) and water (4 mL) in sequence, and stirredat 80° C. for 2 hours. After the reaction was completed, the mixture wascooled to room temperature, condensed and purified by flash columnchromatography (eluting with gradient PE/EA=100:0-0:100) to givecompound B1 as white solid (160 mg, yield: 52.8%). MS (m/z): 362.1[M+H]⁺

(B)2-Fluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol

To a flask were added compound B1 (80 mg, 0.22 mmol), CeCl₃.7H₂O (107mg, 0.29 mmol) and EtOH (5 mL). The mixture was cooled to 0° C. Then,NaBH₄ (11 mg, 0.29 mmol) was added and the mixture was stirred at 0° C.for 2 hours. After the reaction was completed, the mixture was quenchedby the addition of saturated NH₄Cl aqueous solution (2 mL) and water (20mL), and extracted with EtOAc. The organic layer was collected,condensed and purified by flash column chromatography (eluting withgradient PE/EA=100:0-0:100) to give Compound 1 as a white solid (61 mg,yield: 76.3%). MS (m/z): 364.1 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 4.99-4.87 (m, 1H), 4.33-4.23 (m, 1H),4.19-4.07 (m, 1H), 2.61-2.47 (m, 1H), 2.40-2.24 (m, 1H), 1.89-1.73 (m,3H), 1.70-1.61 (m, 1H), 1.38-1.31 (m, 3H), 1.22-1.16 (m, 6H).

The compounds in the below table were prepared according to theprocedure of Compound 1 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 2

418.1 ¹H NMR (400 MHz, CD₃OD): δ 5.01- 4.88 (m, 2H), 4.36-4.24 (m, 1H),2.66- 2.50 (m, 1H), 2.41-2.31 (m, 1H), 1.97- 1.60 (m, 4H), 1.38-1.30 (m,6H). I-3 3

392.1 ¹H NMR (400 MHz, CD₃OD): δ 5.06- 4.90 (m, 1H), 4.61-4.46 (m, 1H),4.37- 4.21 (m, 1H), 4.04-3.87 (m, 2H), 3.85- 3.76 (m, 1H), 3.73-3.60 (m,1H), 2.66- 2.49 (m, 1H), 2.44-2.14 (m, 2H), 2.01- 1.60 (m, 5H),1.45-1.30 (m, 3H). I-8 4

412.1 ¹H NMR (400 MHz, CD₃OD): δ 5.01- 4.87 (m, 1H), 4.37-4.15 (m, 2H),3.05- 2.84 (m, 2H), 2.77-2.49 (m, 3H), 2.42- 2.24 (m, 1H), 1.96-1.56 (m,4H), 1.44- 1.31 (m, 3H). I-30 5

406.1 ¹H NMR (400 MHz, CD₃OD): δ 4.37- 4.22 (m, 3H), 3.02-2.86 (m, 4H),2.73- 2.50 (m, 5H), 2.41-2.25 (m, 1H), 1.91- 1.72 (m, 3H), 1.72-1.62 (m,1H). I-10 6

426.1 ¹H NMR (400 MHz, CD₃OD): δ 5.00- 4.90 (m, 1H), 4.51-4.41 (m, 1H),4.34- 4.25 (m, 1H), 2.62-2.47 (m, 2H), 2.38- 2.17 (m, 3H), 2.14-1.96 (m,2H), 1.90- 1.75 (m, 4H), 1.70-1.61 (m, 1H), 1.40- 1.31 (m, 3H). I-11 7

376.1 ¹H NMR (400 MHz, CD₃OD): δ 5.02- 4.89 (m, 1H), 4.33-4.24 (m, 1H),4.19- 4.06 (m, 1H), 2.63-2.47 (m, 1H), 2.40- 2.25 (m, 1H), 1.92-1.60 (m,4H), 1.40- 1.30 (m, 3H), 1.23-1.15 (m, 6H). I-15 8

390.1 ¹H NMR (400 MHz, CD₃OD): δ 4.99- 4.87 (m, 1H), 4.36-4.22 (m, 1H),3.60- 3.40 (m, 1H), 2.66-2.47 (m, 1H), 2.40- 2.26 (m, 1H), 1.91-1.62 (m,4H), 1.37- 1.31 (m, 3H), 1.27-1.21 (m, 3H), 1.01- 0.85 (m, 1H),0.55-0.15 (m, 4H). I-31 9

392.3 ¹H NMR (400 MHz, CD₃OD): δ 4.99- 4.88 (m, 1H), 4.42-4.34 (m, 1H),4.18- 4.07 (m, 1H), 2.40-2.17 (m, 2H), 1.91- 1.80 (m, 1H), 1.62-1.53 (m,1H), 1.38- 1.31 (m, 3H), 1.22-1.15 (m, 6H), 1.06 (s, 3H), 1.00 (s, 3H).I-2 10

390.1 ¹H NMR (400 MHz, CD₃OD): δ 5.03- 4.89 (m, 1H), 4.37-4.16 (m, 2H),2.64- 2.47 (m, 1H), 2.40-2.24 (m, 1H), 2.04- 1.44 (m, 12H), 1.39-1.31(m, 3H). I-12 11

418.1 ¹H NMR (400 MHz, CD₃OD): δ 5.04- 4.90 (m, 2H), 4.35-4.24 (m, 1H),2.66- 2.52 (m, 1H), 2.43-2.27 (m, 1H), 1.95- 1.60 (m, 4H), 1.43-1.31 (m,6H). I-3 12

378.1 ¹H NMR (400 MHz, CD₃OD): δ 5.00- 4.89 (m, 1H), 4.35-4.23 (m, 1H),3.26- 3.05 (m, 2H), 2.66-2.48 (m, 1H), 2.42- 2.25 (m, 1H), 1.97-1.59 (m,5H), 1.41- 1.30 (m, 3H), 0.96-0.88 (m, 6H). I-13 13

426.1 ¹H NMR (400 MHz, CD₃OD): δ 5.02- 4.89 (m, 1H), 4.35-4.23 (m, 1H),3.63- 3.40 (m, 2H), 2.65-2.51 (m, 3H), 2.47- 2.21 (m, 4H), 1.89-1.61 (m,4H), 1.39- 1.31 (m, 3H). I-14 14

418.1 ¹H NMR (400 MHz, CD₃OD): δ 5.03- 4.90 (m, 2H), 4.36-4.23 (m, 1H),2.67- 2.49 (m, 1H), 2.42-2.26 (m, 1H), 1.94- 1.61 (m, 4H), 1.40-1.31 (m,6H). I-32 15

432.3 ¹H NMR (400 MHz, CD₃OD): δ 5.04- 4.93 (m, 1H), 4.82-4.70 (m, 1H),4.34- 4.23 (m, 1H), 2.65-2.51 (m, 1H), 2.43- 2.28 (m, 1H), 1.91-1.74 (m,4H), 1.71- 1.61 (br, 2H), 1.40-1.31 (m, 3H), 1.04- 0.93 (m, 3H). I-33 16

380.1 ¹H NMR (400 MHz, CD₃OD): δ 5.12- 4.92 (m, 1H), 4.80-4.53 (m, 1H),4.37- 4.26 (m, 1H), 2.87-2.77 (m, 1H), 2.68- 2.51 (m, 1H), 2.46-2.27 (m,1H), 1.97- 1.60 (m, 4H), 1.43-1.31 (m, 3H), 1.2- 1.06 (m, 1H), 1.02-0.87(m, 1H). I-1 17

380.4 ¹H NMR (400 MHz, CD₃OD): δ 5.00- 4.92 (m, 1H), 4.22-4.07 (m, 2H),2.50- 2.27 (m, 2H), 1.95-1.81 (m, 3H), 1.76- 1.66 (m, 1H), 1.41-1.32 (m,3H), 1.23- 1.18 (m, 6H). I-2 18

419.1 ¹H NMR (400 MHz, CD₃OD): δ 5.02- 4.87 (m, 2H), 2.68-2.51 (m, 1H),2.44- 2.28 (m, 1H), 1.92-1.63 (m, 4H), 1.42- 1.30 (m, 6H). I-3 19

407.1 ¹H NMR (400 MHz, CD₃OD): δ 4.38- 4.15 (m, 2H), 3.05-2.85 (m, 4H),2.72- 2.48 (m, 5H), 2.40-2.26 (m, 1H), 1.90- 1.61 (m, 4H). I-10 20

420.2 ¹H NMR (400 MHz, CD₃OD): δ 4.52- 4.38 (m, 1H), 4.33-4.17 (m, 2H),2.99- 2.84 (m, 4H), 2.71-2.48 (m, 5H), 2.37- 2.23 (m, 1H), 2.01-1.82 (m,3H), 1.74- 1.60 (m, 3H). I-10 21

432.3 ¹H NMR (400 MHz, CD₃OD): δ 5.02- 4.89 (m, 2H), 4.53-4.41 (m, 1H),2.77- 2.62 (m, 1H), 2.40-2.27 (m, 1H), 2.02- 1.83 (m, 3H), 1.74-1.61 (m,3H), 1.39- 1.32 (m, 6H). I-3 22

421.1 ¹H NMR (400 MHz, CD₃OD): δ 4.36- 4.16 (m, 2H), 3.00-2.84 (m, 4H),2.73- 2.50 (m, 5H), 2.39-2.21 (m, 1H), 2.01- 1.82 (m, 3H), 1.75-1.59 (m,3H). I-10 23

365.2 ¹H NMR (400 MHz, CD₃OD): δ 4.99- 4.86 (m, 1H), 4.20-4.07 (m, 1H),2.61- 2.47 (m, 1H), 2.37-2.25 (m, 1H), 1.88- 1.62 (m, 4H), 1.37-1.29 (m,3H), 1.20- 1.17 (m, 6H). I-2 24

427.1 ¹H NMR (400 MHz, CD₃OD): δ 4.99- 4.86 (m, 1H), 4.34-4.15 (m, 1H),2.97- 2.83 (m, 2H), 2.73-2.51 (m, 3H), 2.37- 2.25 (m, 1H), 2.01-1.82 (m,3H), 1.72- 1.60 (m, 3H), 1.39-1.13 (m, 3H). I-9 25

310.1 ¹H NMR (400 MHz, CD₃OD): δ 4.36- 4.24 (m, 1H), 4.24-4.00 (m, 2H),2.62- 2.43 (m, 1H), 2.39-2.22 (m, 1H), 1.91- 1.82 (m, 2H), 1.82-1.72 (m,1H), 1.70- 1.60 (m, 1H), 1.19 (s, 12H). I-34 26

378.1 ¹H NMR (400 MHz, CD₃OD): δ 5.19- 4.88 (m, 2H), 4.38-4.22 (m, 1H),2.96 (s, 3H), 2.68-2.49 (m, 1H), 2.43-2.28 (m, 1H), 1.91-1.83 (m, 2H),1.83-1.70 (m, 1H), 1.70-1.59 (m, 1H), 1.35 (d, J = 5.3 Hz, 3H), 1.16 (d,J = 6.5 Hz, 6H). I-35 27

356.1 ¹H NMR (400 MHz, CD₃OD): δ 4.42- 4.13 (m, 2H), 3.02-2.86 (m, 2H),2.83- 2.46 (m, 4H), 2.44-2.21 (m, 1H), 1.92- 1.83 (m, 2H), 1.83-1.60 (m,2H), 0.82- 0.67 (m, 2H), 0.60-0.45 (m, 2H). I-36 28

358.1 ¹H NMR (400 MHz, CD₃OD): δ 4.36- 4.20 (m, 2H), 4.20-4.04 (m, 1H),3.01- 2.84 (m, 2H), 2.71-2.45 (m, 3H), 2.40- 2.23 (m, 1H), 1.90-1.83 (m,2H), 1.83- 1.60 (m, 2H), 1.20 (s, 6H). I-37 29

372.1 ¹H NMR (400 MHz, CD₃OD): δ 4.98- 4.88 (m, 1H), 2.65-2.43 (m, 1H),2.41- 2.23 (m, 1H), 1.92-1.70 (m, 3H), 1.70- 1.59 (m, 1H), 1.37-1.29 (m,3H). I-39 30

372.1 ¹H NMR (400 MHz, CD₃OD): δ 4.97- 4.89 (m, 1H), 2.70-2.42 (m, 1H),2.41- 2.21 (m, 1H), 1.90-1.72 (m, 3H), 1.69- 1.59 (m, 1H), 1.37-1.29 (m,3H). I-40 31

412.1 ¹H NMR (400 MHz, CD₃OD): δ 5.02- 4.89 (m, 1H), 4.38-4.14 (m, 2H),3.03- 2.86 (m, 2H), 2.80-2.49 (m, 3H), 2.44- 2.26 (m, 1H), 1.95-1.59 (m,4H), 1.41- 1.31 (m, 3H). I-9 32

412.1 ¹H NMR (400 MHz, CD₃OD): δ 5.03- 4.90 (m, 1H), 4.38-4.16 (m, 2H),3.02- 2.86 (m, 2H), 2.82-2.50 (m, 3H), 2.43- 2.25 (m, 1H), 1.94-1.60 (m,4H), 1.42- 1.32 (m, 3H). I-54 33

364.1 ¹H NMR (400 MHz, CD₃OD): δ 5.02- 4.90 (m, 1H), 4.38-4.22 (m, 1H),4.18- 4.04 (m, 1H), 2.66-2.49 (m, 1H), 2.39- 2.20 (m, 1H), 2.03-1.58 (m,4H), 1.42- 1.29 (m, 3H), 1.23-1.10 (m, 6H). I-71 34

431.0 ¹H NMR (400 MHz, CD₃OD) δ 8.93- 8.75 (m, 2H), 7.98-7.93 (m, 1H),7.83- 8.77 (m, 1H), 4.37-4.29 (m, 1H), 2.72- 2.60 (m, 1H), 2.47-2.35 (m,341H), 1.92-1.85 (m, 2H), 1.84-1.75 (m, 1H), 1.73-1.65 (m, 1H), 1.32 (s,9H). I-75 200

384.1 ¹H NMR (400 MHz, CD₃OD): δ 9.55 (s, 1H), 7.91-7.78 (m, 1H),7.64-7.48 (m, 1H), 7.33-7.13 (m, 1H), 6.62-6.47 (m, 1H), 4.41-4.14 (m,2H), 2.72-2.32 (m, 2H), 1.91-1.63 (m, 4H), 1.29-1.20 (m, 6H). I-5 205

390.1 ¹H NMR (400 MHz, CD₃OD): δ 8.59- 8.34 (m, 2H), 4.39-4.28 (m, 1H),2.74- 2.61 (m, 1H), 2.55 (s, 3H), 2.51-2.37 (m, 1H), 1.98-1.66 (m, 4H),1.31 (s, 9H). I-29 219

444.2 ¹H NMR (400 MHz, CD₃OD): δ 5.05- 4.86 (m, 2H), 3.49-3.39 (m, 1H),2.73- 2.58 (m, 1H), 2.53-2.38 (m, 1H), 2.22- 2.09 (m, 1H), 1.39-1.32 (m,6H), 1.03- 0.94 (m, 1H), 0.78-0.68 (m, 1H), 0.51- 0.40 (m, 3H). I-3 229

401.0 ¹H NMR (400 MHz, CD₃OD): δ 9.34-9.19 (m, 1H), 8.60-8.36 (m, 1H),7.73-7.54 (m, 2H), 4.39-4.30 (m, 1H), 4.26-4.15 (m, 1H), 2.72-2.56 (m,1H), 2.48-2.33 (m, 1H), 1.93-1.63 (m, 4H), 1.29-1.21 (m, 6H). I-81

Compound 356-(2,3-Difluorocyclohex-1-en-1-yl)-N²-isopropyl-N⁴-((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

At 0° C., Compound 1 (20 mg, 0.06 mmol) was dissolved in DCM (3 mL), andDAST (17 mg, 0.12 mmol) was added. The mixture was stirred at 0° C. for2.5 hours. After the reaction was completed, the mixture was quenched bythe addition of saturated NH₄Cl aqueous solution (5 mL) and water (5mL), and extracted with EtOAc. The organic layer was collected,condensed and purified by flash column chromatography (eluting withgradient PE/EA=100:0-0:100) to give the title compound as a white solid(14 mg, yield: 70%). MS (m/z): 366.2 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 5.15-4.86 (m, 2H), 4.21-4.08 (m, 1H),2.70-2.51 (m, 1H), 2.42-2.26 (m, 1H), 2.20-2.08 (m, 1H), 1.92-1.67 (m,3H), 1.37-1.31 (m, 3H), 1.21-1.16 (m, 6H).

The compounds in the below table were prepared according to theprocedure of Compound 35 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 36

348.0 ¹H NMR (400 MHz, CD₃OD): δ 7.16- 6.94 (m, 1H), 5.25-5.06 (m, 1H),5.05- 4.89 (m, 1H), 4.27-4.06 (m, 1H), 2.63- 2.26 (m, 2H), 1.95-1.63 (m,4H), 1.39- 1.30 (d, J = 5.2 Hz, 3H), 1.24-1.16 (m, 6H). Comp. 124 37

348.3 ¹H NMR (400 MHz, CD₃OD): δ 7.26- 7.00 (m, 1H), 5.08-4.85 (m, 2H),4.26- 4.07 (m, 1H), 2.87-2.70 (m, 1H), 2.68- 2.53 (m, 1H), 2.44-2.26 (m,2H), 1.95- 1.80 (m, 2H), 1.36-1.30 (m, 3H), 1.20- 1.16 (m, 6H). Comp.144 38

348.3 ¹H NMR (400 MHz, CD₃OD): δ 7.13- 6.85 (m, 1H), 5.03-4.85 (m, 2H),4.24- 4.07 (m, 1H), 2.63-2.35 (m, 4H), 2.01- 1.82 (m, 2H), 1.36-1.31 (m,3H), 1.20- 1.16 (m, 6H). Com. 145

Compound 39(*)3-(4,6-Bis((3,3-difluorocyclobutyl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohept-2-en-1-ol

Under nitrogen atmosphere, 1 mol/L (S)—CBS/THF solution (1.4 mL, 1.4mmol) was added to dry THF (5 mL) under ice bath cooling ° C., then tothe solution was added 2 mol/L BH₃.Me₂S/THF solution (1.4 mL, 2.8 mmol)in one-portion. After stirred for 2 minutes,3-(4,6-bis((3,3-difluorocyclobutyl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohept-2-en-1-one (prepared according to the procedure of Compound 1using Intermediate I-10, 600 mg, 1.4 mmol) in THF (3 mL) was addeddropwise and the mixture was stirred in ice-bath for 1 hour. Then, MeOH(0.5 mL), EtOAc (10 mL) and water (20 mL) were added to the reactionmixture. The organic layer was collected. The aqueous was extracted withEtOAc (10 mL). The organic layers were combined, dried over Na₂SO₄ andfiltered. The filtrate was condensed and purified by flash columnchromatography (eluting with gradient PE/EA=100:0-0:100) to give thetitle compound as white solid (60 mg, yield: 10%). MS (m/z): 420.1[M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 4.52-4.38 (m, 1H), 4.33-4.17 (m, 2H),2.99-2.84 (m, 4H), 2.71-2.48 (m, 5H), 2.37-2.23 (m, 1H), 2.01-1.82 (m,3H), 1.74-1.60 (m, 3H).

The compounds in the below table were prepared according to theprocedure of Compound 39 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 40

426.1 ¹H NMR (400 MHz, CD₃OD): δ 4.98- 4.87 (m, 1H), 4.51-4.41 (m, 1H),4.31- 4.16 (m, 1H), 2.97-2.84 (m, 2H), 2.73- 2.49 (m, 3H), 2.37-2.23 (m,1H), 2.00- 1.81 (m, 3H), 1.72-1.58 (m, 3H), 1.39- 1.30 (m, 3H). I-9 41

400.1 ¹H NMR (400 MHz, CD₃OD): δ 5.00- 4.89 (m, 1H), 4.69-4.44 (m, 5H),4.34- 4.22 (m, 1H), 2.65-2.50 (m, 1H), 2.40- 2.25 (m, 1H), 1.89-1.57 (m,4H), 1.38- 1.29 (m, 3H). I-72 42

388.2 ¹H NMR (400 MHz, CD₃OD): δ 5.00- 4.89 (m, 1H), 4.33-4.21 (m, 1H),3.13- 2.99 (m, 1H), 2.62-2.47 (m, 1H), 2.37- 2.18 (m, 1H), 1.87-1.61 (m,4H), 1.37- 1.30 (m, 3H), 1.25-1.19 (m, 1H), 1.00- 0.71 (m, 5H). I-73 43

376.1 ¹H NMR (400 MHz, CD₃OD): δ 4.51- 4.18 (m, 5H), 3.01-2.82 (m, 2H),2.71- 2.45 (m, 3H), 2.38-2.20 (m, 1H), 1.87- 1.59 (m, 4H), 1.27-1.19 (m,3H). I-74 44

438.1 ¹H NMR (400 MHz, CD₃OD): δ 8.47- 8.11 (m, 2H), 7.66 (s, 1H),7.49-7.37 (m, 1H), 7.18-7.05 (m, 1H), 5.08-4.94 (m, 1H), 4.40-4.27 (m,1H), 2.75-2.61 (m, 1H), 2.51-2.37 (m, 1H), 1.92-1.66 (m, 4H), 1.43-1.37(m, 3H). I-56 45

384.1 ¹H NMR (400 MHz, CD₃OD): δ 8.37- 8.29 (br, 1H), 8.29-8.16 (m, 1H),7.65 (s, 1H), 7.47-7.38 (m, 1H), 7.15-6.99 (m, 1H), 4.37-4.18 (m, 2H),2.74-2.56 (m, 1H), 2.51-2.34 (m, 1H), 1.90-1.64 (m, 4H), 1.29-1.22 (m,6H). I-57 46

375.1 ¹H NMR (400 MHz, CD₃OD): δ 8.63- 8.10 (m, 1H), 7.69-7.53 (m, 1H),6.52 (d, J = 9.6 Hz, 1H), 4.36-4.24 (m, 1H), 4.22-4.04 (m, 1H), 3.57 (s,3H), 2.68- 2.50 (m, 1H), 2.43-2.28 (m, 1H), 1.89- 1.61 (m, 4H),1.23-1.16 (m, 6H). I-58 47

409.2 ¹H NMR (400 MHz, CD₃OD): δ 8.48- 8.19 (m, 1H), 8.14-8.04 (m, 1H),7.65- 7.46 (m, 1H), 4.38-4.26 (m, 1H), 2.73- 2.58 (m, 1H), 2.49-2.34 (m,1H), 1.91- 1.64 (m, 4H), 1.32 (s, 9H). I-59 48

375.2 ¹H NMR (400 MHz, CD₃OD): δ 7.50- 7.42 (m, 1H), 7.26-7.20 (m, 1H),6.81- 6.68 (m, 1H), 4.36-4.13 (m, 2H), 3.48 (s, 3H), 2.74-2.55 (m, 1H),2.46-2.32 (m, 1H), 1.89-1.62 (m, 4H), 1.27-1.17 (m, 6H). I-60 49

356.1 ¹H NMR (400 MHz, CD₃OD): δ 4.39- 4.18 (m, 2H), 2.99-2.86 (m, 2H),2.80- 2.46 (m, 4H), 2.39-2.23 (m, 1H), 1.89- 1.82 (m, 2H), 1.81-1.62 (m,2H), 0.79- 0.67 (m, 2H), 0.55-0.48 (m, 2H). I-36 50

370.1 ¹H NMR (400 MHz, CD₃OD): δ 4.45- 4.14 (m, 2H), 3.05-2.82 (m, 2H),2.79- 2.23 (m, 5H), 1.91-1.61 (m, 4H), 1.18- 0.45 (m, 6H). I-38 51

358.1 ¹H NMR (400 MHz, CD₃OD): δ 4.35- 4.20 (m, 2H), 4.20-4.06 (m, 1H),2.98- 2.86 (m, 2H), 2.70-2.45 (m, 3H), 2.38- 2.23 (m, 1H), 1.89-1.82 (m,2H), 1.81- 1.60 (m, 2H), 1.19 (s, 6H). I-37 52

371.1 ¹H NMR (400 MHz, CD₃OD): δ 4.99- 4.87 (m, 1H), 4.33-4.23 (m, 1H),2.64- 2.45 (m, 1H), 2.40-2.21 (m, 1H), 1.89- 1.71 (m, 3H), 1.70-1.58 (m,1H), 1.36- 1.30 (m, 3H). I-39 53

371.1 ¹H NMR (400 MHz, CD₃OD): δ 4.98- 4.88 (m, 1H), 4.35-4.19 (m, 1H),2.63- 2.44 (m, 1H), 2.44-2.21 (m, 1H), 1.93- 1.70 (m, 3H), 1.70-1.53 (m,1H), 1.39- 1.29 (m, 3H). 1-40 54

420.1 ¹H NMR (400 MHz, CD₃OD): δ 8.60- 8.22 (m, 2H), 8.09-7.74 (m, 1H),4.38- 4.27 (m, 1H), 2.75-2.58 (m, 1H), 2.48- 2.33 (m, 1H), 1.91-1.75 (m,3H), 1.73- 1.64 (m, 1H). I-41 55

365.1 ¹H NMR (400 MHz, CD₃OD): δ 4.36- 4.15 (m, 2H), 3.02-2.81 (m, 2H),2.73- 2.41 (m, 3H), 2.40-2.19 (m, 1H), 1.89- 1.71 (m, 3H), 1.70-1.59 (m,1H). I-42 56

360.1 ¹H NMR (400 MHz, CD₃OD): δ 4.32- 4.19 (m, 2H), 4.19-4.04 (m, 1H),2.98- 2.83 (m, 2H), 2.72-2.43 (m, 3H), 2.39- 2.21 (m, 1H), 1.80-1.70 (m,1H), 1.68- 1.58 (m, 1H), 1.25-1.11 (br, 6H). I-37 57

348.1 ¹H NMR (400 MHz, CD₃OD): δ 8.16- 7.44 (m, 2H), 4.38-4.24 (m, 1H),4.24- 4.10 (m, 1H), 3.84 (s, 3H), 2.69-2.49 (m, 1H), 2.47-2.27 (m, 1H),1.91-1.74 (m, 3H), 1.72-1.61 (m, 1H), 1.29-1.18 (m, 6H). I-43 58

388.0 ¹H NMR (400 MHz, CD₃OD): δ 8.61- 8.24 (m, 2H), 8.04-7.81 (m, 1H),4.39- 4.27 (m, 1H), 2.75-2.58 (m, 1H), 2.51- 2.31 (m, 1H), 1.92-1.75 (m,3H), 1.73- 1.64 (m, 1H). I-44 59

348.1 ¹H NMR (400 MHz, CD₃OD): δ 8.39- 8.25 (m, 2H), 7.86-7.79 (m, 1H),7.13- 7.02 (m, 1H), 6.42-6.36 (m, 1H), 4.37- 4.28 (m, 1H), 4.26-4.15 (m,1H), 2.72- 2.55 (m, 1H), 2.47-2.34 (m, 1H), 1.91- 1.85 (m, 2H),1.85-1.74 (m, 1H), 1.73- 1.64 (m, 1H), 1.28-1.21 (m, 6H). I-45 60

400.1 ¹H NMR (400 MHz, CD₃OD): δ 9.07- 8.95 (m, 1H), 8.49-8.43 (m, 1H),7.68- 7.57 (m, 2H), 7.57-7.52 (m, 1H), 7.30- 7.25 (m, 1H), 4.39-4.28 (m,1H), 2.75- 2.59 (m, 1H), 2.48-2.35 (m, 1H), 1.92- 1.84 (m, 2H),1.84-1.76 (m, 1H), 1.74- 1.65 (m, 1H), 1.33 (s, 9H). I-46 61

409.1 ¹H NMR (400 MHz, CD₃OD): δ 8.91- 8.64 (m, 1H), 8.27-8.16 (m, 1H),7.11- 6.99 (m, 1H), 4.38-4.28 (m, 1H), 2.74- 2.56 (m, 1H), 2.48-2.33 (m,1H), 1.92- 1.84 (m, 2H), 1.84-1.76 (m, 1H), 1.73- 1.64 (m, 1H), 1.33 (s,9H). I-47 62

395.1 ¹H NMR (400 MHz, CD₃OD): δ 8.75- 8.53 (m, 1H), 8.25-8.15 (m, 1H),7.83- 7.73 (m, 2H), 7.66-7.59 (m, 1H), 7.45- 7.36 (m, 1H), 4.39-4.28 (m,1H), 4.26- 4.15 (m, 1H), 2.73-2.56 (m, 1H), 2.48- 2.33 (m, 1H),1.92-1.85 (m, 2H), 1.85- 1.75 (m, 1H), 1.72-1.63 (m, 1H), 1.27- 1.20 (m,6H). I-48 63

398.1 ¹H NMR (400 MHz, CD₃OD): δ 8.18- 8.11 (m, 1H), 8.09-8.01 (m, 1H),7.52- 7.46 (m, 1H), 7.46-7.32 (m, 1H), 4.35- 4.26 (m, 1H), 4.22-4.16 (m,1H), 4.15 (s, 3H), 2.70-2.29 (m, 2H), 1.90-1.84 (m, 2H), 1.84-1.74 (m,1H), 1.71-1.63 (m, 1H), 1.25-1.18 (m, 6H). I-49 64

398.1 ¹H NMR (400 MHz, CD₃OD): δ 8.25- 8.10 (m, 1H), 7.94-7.86 (m, 1H),7.66- 7.39 (m, 2H), 4.35-4.25 (br, 1H), 4.23- 4.11 (m, 1H), 4.02 (s,3H), 2.70-2.51 (m, 1H), 2.45-4.28 (m, 1H), 1.91-1.83 (m, 2H), 1.83-1.74(m, 1H), 1.71-1.62 (m, 1H), 1.26-1.17 (m, 6H). I-50 65

401.1 ¹H NMR (400 MHz, CD₃OD): δ 8.89- 8.84 (m, 1H), 8.83-8.66 (m, 1H),7.98- 7.91 (m, 1H), 7.82-7.70 (m, 1H), 4.36- 4.28 (m, 1H), 4.25-4.18 (m,1H), 2.71- 2.56 (m, 1H), 2.47-2.34 (m, 1H), 1.91- 1.85 m, 2H), 1.85-1.77(m, 1H), 1.72- 1.64 (m, 1H), 1.28-1.22 (m, 6H). I-51 66

385.1 ¹H NMR (400 MHz, CD₃OD/CDCl3 = 2/1): δ 8.63-8.54 (m, 1H),7.62-7.57 (m, 2H), 7.13-7.04 (m, 1H), 4.38-4.12 (m, 2H), 2.70-2.32 (m,2H), 1.91-1.84 (m, 2H), 1.84-1.74 (m, 1H), 1.73-1.63 (m, 1H), 1.25-1.20(m, 6H). I-52 67

414.1 ¹H NMR (400 MHz, CD₃OD): δ 8.38- 8.22 (m, 2H), 7.89-7.76 (m, 1H),7.12- 7.01 (m, 1H), 6.45-6.34 (m, 1H), 4.38- 4.27 (m, 1H), 3.51-3.42 (m,2H), 2.70- 2.56 (m, 1H), 2.46-2.34 (m, 1H), 1.91- 1.84 (m, 2H),1.83-1.74 (m, 1H), 1.72- 1.64 (m, 1H), 1.26-1.18 (m, 6H). I-53 68

449.1 ¹H NMR (400 MHz, CD₃OD): δ 8.86- 7.07 (m, 6H), 5.19-4.97 (m, 1H),4.41- 4.27 (m, 1H), 2.78-2.60 (m, 1H), 2.53- 2.37 (m, 1H), 1.94-1.78 (m,3H), 1.76- 1.65 (m, 1H), 1.45-1.36 (m, 3H). I-62 69

418.1 ¹H NMR (400 MHz, CD₃OD): δ 5.00- 4.87 (m, 2H), 4.36-4.22 (m, 1H),2.65- 2.51 (m, 1H), 2.43-2.29 (m, 1H), 1.89- 1.60 (m, 4H), 1.38-1.29 (m,6H). I-32 70

443.1 ¹H NMR (400 MHz, CD₃OD): δ 8.64- 7.73 (m, 3H), 4.43-4.27 (m, 1H),3.53- 3.43 (m, 2H), 2.79-2.61 (m, 1H), 2.52- 2.36 (m, 1H), 1.92-1.67 (m,4H), 1.24- 1.16 (m, 6H). I-66 71

443.1 ¹H NMR (400 MHz, CD₃OD): δ 8.55- 8.36 (m, 2H). 8.01-7.90 (m, 1H),4.41- 4.30 (m, 1H), 2.77-2.62 (m, 1H), 2.52- 2.32 (m, 1H), 1.96-1.64 (m,4H), 1.31 (s, 9H). I-63 72

465.0 ¹H NMR (400 MHz, CD₃OD): δ 8.58- 7.52 (m, 5H), 7.14-6.94 (m, 2H),4.42- 4.27 (m, 1H), 2.80-2.65 (m, 1H), 2.56- 2.37 (m, 1H), 1.94-1.66 (m,4H). I-64 73

393.1 ¹H NMR (400 MHz, CD₃OD): δ 8.09- 7.85 (m, 2H), 7.51-7.39 (m, 1H),4.41- 4.26 (m, 1H), 2.74-2.57 (m, 1H), 2.49- 2.32 (m, 1H), 1.96-1.64 (m,4H), 1.32- 1.29 (m, 9H). I-65 74

363.1 ¹H NMR (400 MHz, CD₃OD): δ 8.02- 7.88 (m, 1H), 7.85-7.72 (m, 1H),7.52- 7.39 (m, 1H), 4.39-4.29 (m, 1H), 4.26- 4.12 (m, 1H), 2.76-2.56 (m,1H), 2.49- 2.32 (m, 1H), 1.99-1.61 (m, 4H), 1.28- 1.20 (m, 6H). I-67 75

444.1 ¹H NMR (400 MHz, CD₃OD): δ 9.18- 8.77 (m, 2H), 4.45-4.24 (m, 1H),2.81- 2.64 (m, 1H), 2.53-2.34 (m, 1H), 2.00- 1.66 (m, 4H), 1.37-1.26 (m,9H). I-68 76

384.1 ¹H NMR (400 MHz, CD₃OD): δ 9.63- 9.01 (m, 1H), 7.74 (s, 1H),7.54-7.48 (m, 1H), 7.47-7.40 (m, 1H), 7.38-7.22 (m, 1H), 4.39-4.29 (m,1H), 4.25-4.12 (m, 1H), 2.73-2.55 (m, 1H), 2.50-2.31 (m, 1H), 1.96-1.63(m, 4H), 1.29-1.18 (m, 6H). I-69 77

388.1 ¹H NMR (400 MHz, CD₃OD): δ 6.59- 6.32 (m, 1H), 4.36-4.27 (m, 1H),4.23- 4.10 (m, 1H), 4.03-3.90 (m, 2H), 2.82- 2.72 (m, 2H), 2.65-2.51 (m,1H), 2.46- 2.29 (m, 1H), 2.09-1.97 (m, 2H), 1.90- 1.63 (m, 6H),1.25-1.16 (m, 6H). I-70 78

378.2 ¹H NMR (400 MHz, CD₃OD): δ 5.04- 4.89 (m, 1H), 4.34-4.24 (m, 1H),3.25- 3.07 (m, 2H), 2.65-2.48 (m, 1H), 2.40- 2.20 (m, 1H), 1.96-1.59 (m,5H), 1.38- 1.30 (m, 3H), 0.95-0.87 (m, 6H). I-13 79

404.1 ¹H NMR (400 MHz, CD₃OD): δ 5.03- 4.90 (m, 1H), 4.35-4.26 (m, 1H),4.21- 4.00 (m, 2H), 2.65-2.49 (m, 1H), 2.43- 2.24 (m, 1H), 1.93-1.59 (m,4H), 1.42- 1.30 (m, 3H). I-76 80

376.1 ¹H NMR (400 MHz, CD₃OD): δ 5.50- 4.87 (m, 1H), 4.34-4.23 (m, 1H),3.26- 3.14 (m, 2H), 2.62-2.47 (m, 1H), 2.39- 2.22 (m, 1H), 1.89-1.82 (m,2H), 1.82- 1.73 (m, 1H), 1.71-1.63 (br, 1H), 1.37- 1.31 (m, 3H),1.14-0.99 (m, 1H), 0.51- 0.42 (m, 2H), 0.26-0.19 (m, 2H). I-77 81

364.1 ¹H NMR (400 MHz, CD₃OD): δ 5.01- 4.87 (m, 1H), 4.34-4.22 (m, 1H),3.37- 3.30 (m, 1H), 3.28-3.23 (m, 1H), 2.62- 2.48 (m, 1H), 2.38-2.22 (m,1H), 1.88- 1.82 (m, 2H), 1.82-1.72 (m, 1H), 1.69- 1.62 (m, 1H),1.62-1.53 (m, 2H), 1.37- 1.30 (m, 3H), 0.96-0.89 (m, 3H). I-78 199

431.0 ¹H NMR (400 MHz, CD₃OD): δ 8.91- 8.85 (m, 1H), 8.80-8.66 (m, 1H),7.99- 7.91 (m, 1H), 7.82-7.72 (m, 1H), 4.38- 4.28 (m, 1H), 3.53-3.40 (m,2H), 2.72- 2.58 (m, 1H), 2.48-4.34 (m, 1H), 1.93- 1.85 (m, 2H),1.84-1.76 (m, 1H), 1.73- 1.65 (m, 1H), 1.25-1.19 (m, 6H). I-79 204

389.1 ¹H NMR (400 MHz, CD₃OD): δ 8.30- 8.09 (m, 1H), 7.93-7.58 (m, 2H),4.40- 4.28 (m, 1H), 2.75-2.60 (m, 1H), 2.52- 2.36 (m, 4H), 1.95-1.65 (m,4H), 1.32 (s, 9H). I-28 224

362.0 ¹H NMR (400 MHz, CD₃OD): δ 5.12- 4.89 (m, 1H), 4.36-4.21 (m, 1H),2.81- 2.66 (m, 1H), 2.65-2.46 (m, 1H), 2.41- 2.21 (m, 1H), 1.90-1.82 (m,2H), 1.82- 1.72 (m, 1H), 1.70-1.59 (m, 1H), 1.39- 1.29 (m, 3H),0.77-0.68 (m, 2H), 0.55- 0.47 (m, 2H). I-16 240

368.0 ¹H NMR (400 MHz, CD₃OD): δ 4.98- 4.90 (m, 1H), 4.60-4.52 (m, 1H),4.49- 4.40 (m, 1H), 4.35-4.20 (m, 1H), 3.74- 3.54 (m, 2H), 2.68-2.45 (m,1H), 2.43- 2.22 (m, 1H), 1.91-1.81 (m, 2H), 1.81- 1.72 (m, 1H),1.70-1.60 (m, 1H), 1.34 (s, 3H). I-83 241

398.0 ¹H NMR (400 MHz, CD₃OD): δ 4.35- 4.17 (m, 2H), 4.16-4.04 (m, 2H),3.00- 2.84 (m, 2H), 2.71-2.48 (m, 3H), 2.42- 2.26 (m, 1H), 1.91-1.82 (m,2H), 1.82- 1.73 (m, 1H), 1.70-1.60 (m, 1H). I-84

Compounds 82 and 83(*)3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-6,6-D₂-1-oland3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1,6,6-D₃-1-ol

(A)3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one-6,6-D₂

To a solution of3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one(prepared according to the procedure of Compound 1 using IntermediateI-3, 114 mg, 0.27 mmol) in 1,4-dioxane (6 mL) was added D₂O (2 mL) andK₂CO₃ (75 mg, 0.54 mmol). The mixture was stirred at 80° C. for 4.5hours. Then, the solvent was removed in vacuo and the residue waspurified by flash column chromatography (eluting with gradientPE/EA=100:0-0:100) to afford the title compound as yellow oil (64 mg,yield: 56%). MS (m/z): 418.0 [M+H]⁺

(B)(*)3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-6,6-D₂-1-ol

Compound 82 was prepared according to the procedure of Compound 39. MS(m/z): 420.1 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 5.00-4.87 (m, 2H), 4.32-4.23 (m, 1H),2.63-2.53 (m, 1H), 2.37-2.26 (m, 1H), 1.81-1.69 (m, 1H), 1.67-1.60 (m,1H), 1.37-1.31 (m, 6H).

(C)3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1,6,6-D₃-1-ol

Compound 83 was prepared according to the procedure of Compound 1 step(B), using NaBD₄. MS (m/z): 421.1 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 5.00-4.87 (m, 2H), 2.63-2.53 (m, 1H),2.37-2.26 (m, 1H), 1.81-1.69 (m, 1H), 1.67-1.60 (m, 1H), 1.37-1.31 (m,6H).

The compounds in the below table were prepared according to theprocedure of Compound 82 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 84

414.1 ¹H NMR (400 MHz, CD₃OD): δ 4.98-4.89 (m, 1H), 4.35-4.13 (m, 2H),3.02-2.81 (m, 2H), 2.75-2.46 (m, 3H), 2.44-2.24 (m, 1H), 1.82- 1.71 (m,1H), 1.69-1.58 (m, 1H), 1.38-1.28 (m, 3H). I-54 85

408.1 ¹H NMR (400 MHz, CD₃OD): δ 4.36-4.14 (m, 3H), 2.98-2.85 (m, 4H),2.67-2.46 (m, 5H), 2.39-2.22 (m, 1H), 1.82-1.71 (m, 1H), 1.68- 1.57 (m,1H). I-10 86

422.1 ¹H NMR (400 MHz, CD₃OD): δ 8.60-8.23 (m, 2H), 8.10-7.75 (m, 1H),4.36-4.28 (m, 1H), 2.72-2.56 (m, 1H), 2.48-2.33 (m, 1H), 1.83- 1.73 (m,1H), 1.71-1.63 (m, 1H). I-41 87

420.0 ¹H NMR (400 MHz, CD₃OD): δ 5.02-4.88 (m, 2H), 4.34-4.24 (m, 1H),2.60-2.48 (m, 1H), 2.42-2.30 (m, 1H), 1.88-1.72 (m, 1H), 1.70- 1.58 (m,1H), 1.36-1.31 (m, 6H). I-32 89

445.1 ¹H NMR (400 MHz, CD₃OD): δ 8.54-8.35 (m, 2H), 8.03-7.83 (m, 1H),4.40-4.24 (m, 1H), 2.74-2.60 (m, 1H), 2.48-2.32 (m, 1H), 1.85- 1.74 (m,1H), 1.71-1.60 (m, 1H), 1.31 (s, 9H). I-63

The compounds in the below table were prepared according to theprocedure of Compound 83 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 90

415.1 ¹H NMR (400 MHz, CD₃OD): δ 4.98-4.89 (m, 1H), 4.35-4.13 (m, 1H),3.02-2.81 (m, 2H), 2.75-2.46 (m, 3H), 2.44-2.24 (m, 1H), 1.82- 1.71 (m,1H), 1.69-1.58 (m, 1H), 1.38-1.28 (m, 3H). I-54 91

409.1 ¹H NMR (400 MHz, CD₃OD): δ 4.36-4.14 (m, 2H), 2.98-2.85 (m, 4H),2.67-2.46 (m, 5H), 2.39-2.22 (m, 1H), 1.82-1.71 (m, 1H), 1.68- 1.57 (m,1H). I-10 92

361.1 ¹H NMR (400 MHz, CD₃OD): δ 4.34-4.18 (m, 1H), 4.18-4.00 (m, 1H),3.01-2.81 (m, 2H), 2.72-2.41 (m, 3H), 2.41-2.18 (m, 1H), 1.80- 1.70 (m,1H), 1.69-1.58 (m, 1H), 1.25-1.11 (br, 6H). I-37

Compound 93(*)3-(4-Amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-ol

(A)(R)-2-fluoro-3-(4-((4-methoxybenzyl)amino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one(B2)

The title Compound B2 was prepared according to the procedure ofCompound 1, using Intermediate I-55. MS (m/z): 440.1 [M+H]⁺

(B)(R)-3-(4-amino-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-one(B3)

A solution of Compound B2 (1.1 g, 2.5 mmol) in TFA (10 mL) was stirredat reflux for 4 hours. The solvent was removed. The residue was washedwith saturated NaHCO₃ aqueous solution and purified by flash columnchromatography (eluting with gradient PE/EA=100:0-0:100) to giveCompound B3 as pale yellow solid. MS (m/z): 320.0[M+H]⁺

(C)(*)3-(4-Amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-ol

Compound 93 was prepared according to the procedure of Compound 39. MS(m/z): 322.0 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 5.01-4.89 (m, 1H), 4.38-4.19 (m, 1H),2.62-2.47 (m, 1H), 2.38-2.24 (m, 1H), 1.89-1.61 (m, 4H), 1.36-1.29 (m,3H).

Compounds 95 and 962,6-Difluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol,optically pure diastereoisomers

(A)2,6-difluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one(B4)

Under nitrogen atmosphere, to 1 mol/L of LiHMDS/THF solution (14.85 mL,14.85 mmoL) was added dropwise a solution of Compound 123 (1.2 g, 3.30mmol) in THF (20 mL) at −78° C. The mixture was stirred at 0° C. for 2hours. A solution of NFSI (3.12 g, 9.90 mmol) in THF added drop-wiseslowly, then the mixture was warmed to room temperature and stirred for3 hours. After the reaction was completed, the mixture was quenched bythe addition of saturated NH₄Cl aqueous solution (30 mL). The organiclayer was collected and the aqueous was extracted with EtOAc. Theorganic layers were combined, dried over anhydrous Na₂SO₄ and filtered.The filtrate was condensed in vacuo and purified by flash columnchromatography (eluting with gradient PE/EA=100:0-0:100) to giveCompound B4 as white solid (190 mg, yield: 15.2%). MS (m/z): 380.2[M+H]⁺

(B)2,6-Difluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol

Compounds 95 and 96 were prepared according to the procedure of Compound39, and purified by preparative TLC (eluting with PE/EA=2/1).

Compound 95, Rf≈0.55, MS (m/z): 382.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): δ4.97-4.90 (m, 1H), 4.72-4.55 (m, 1H), 4.38-4.03 (m, 2H), 2.63-2.46 (m,2H), 2.06-1.90 (m, 2H), 1.38-1.31 (m, 3H), 1.23-1.13 (s, 6H).

Compound 96, Rf≈0.50, MS (m/z): 382.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): δ4.97-4.90 (m, 1H), 4.71-4.55 (m, 1H), 4.51-4.40 (m, 1H), 4.20-4.05 (m,1H), 2.76-2.58 (m, 1H), 2.48-2.31 (m, 1H), 2.15-2.01 (m, 1H), 1.98-1.81(m, 1H), 1.40-1.30 (m, 3H), 1.22-1.12 (m, 6H).

The compounds in the below table were prepared according to theprocedure of Compounds 95 and 96 using the corresponding intermediatesand reagents under appropriate conditions that will be recognized byPOSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 97

436.2 ¹H NMR (400 MHz, CD₃OD): δ 4.98-4.88 (m, 2H), 4.82-4.63 (m, 1H),4.35-4.18 (m, 1H), 2.64-2.49 (m, 2H), 2.06-1.90 (m, 2H), 1.37- 1.31 (m,6H). I-3 98

436.1 ¹H NMR (400 MHz, CD₃OD): δ 5.03-4.89 (m, 2H), 4.80-4.65 (m, 1H),4.55-4.38 (m, 1H), 2.80-2.62 (m, 1H), 2.52-2.34 (m, 1H), 2.17- 2.02 (m,1H), 1.98-1.84 (m, 1H), 1.40-1.29 (m, 6H). I-3 201

424.2 ¹H NMR (400 MHz, CD₃OD): δ 4.79-4.64 (m, 1H), 4.37-4.15 (m, 3H),2.99-2.83 (m, 4H), 2.70-2.47 (m, 6H), 2.06-1.88 (m, 2H). I-10 202

424.2 ¹H NMR (400 MHz, CD₃OD): δ 4.81-4.64 (m, 1H), 4.52-4.38 (m, 1H),4.34-4.17 (m, 2H), 2.99-2.83 (m, 4H), 2.70-2.32 (m, 6H), 2.13- 2.01 (m,1H), 1.96-1.81 (m, 1H). I-10 225

394.2 ¹H NMR (400 MHz, CD₃OD): δ 5.01-4.90 (m, 1H), 4.79-4.62 (m, 1H),4.35-4.19 (m, 1H), 3.27-3.11 (m, 2H), 2.65-2.43 (m, 2H), 2.07- 1.87 (m,2H), 1.40-1.29 (m, 3H), 1.13-1.00 (m, 1H), 0.55-0.40 (m, 2H), 0.31-0.15(m, 2H). I-77 226

394.2 ¹H NMR (400 MHz, CD₃OD): δ 5.00-4.89 (m, 1H), 4.80-4.64 (m, 1H),4.51-4.37 (m, 1H), 3.27-3.09 (m, 2H), 2.78-2.57 (m, 1H), 2.52- 2.30 (m,1H), 2.15-2.01 (m, 1H), 1.97-1.80 (m, 1H), 1.40-1.27 (m, 3H), 1.13-0.98(m, 1H), 0.55-0.40 (m, 2H), 0.30-0.14 (m, 2H). I-77 227

430.0 ¹H NMR (400 MHz, CD₃OD): δ 5.01-4.90 (m, 1H), 4.80-4.63 (m, 1H),4.35-4.11 (m, 2H), 3.01-2.86 (m, 2H), 2.55 (s, 4H), 2.09-1.92 (m, 2H),1.42-1.31 (m, 3H). I-9 228

430.0 ¹H NMR (400 MHz, CD₃OD): δ 5.05-4.88 (m, 1H), 4.82-4.64 (m, 1H),4.54-4.40 (m, 1H), 4.36-4.17 (m, 1H), 3.00-2.84 (m, 2H), 2.77- 2.34 (m,4H), 2.16-2.02 (m, 1H), 1.96-1.83 (m, 1H), 1.41-1.30 (m, 3H). I-9 230&231

382.1 382.0 ¹H NMR (400 MHz, DMSO-d₆): δ 7.89-7.69 (m, 1H), 7.54-7.36(m, 1H), 5.82-5.56 (m, 1H), 4.93-4.59 (m, 2H), 4.39-4.28 (m, 1H), 3.22-3.10 (m, 2H), 2.56-2.39 (m, 1H), 2.38-2.20 (m, 1H), 1.98-1.88 (m, 1H),1.86-1.73 (m, 1H), 1.50-1.41 (m, 2H), 1.29-1.23 (m, 3H), 0.86- 0.79 (m,3H). I-18 I-18

¹H NMR (400 MHz, DMSO-d₆): δ 7.92-7.69 (m, 1H), 7.60-7.34 (m, 1H),6.11-5.82 (m, 1H), 4.96-4.59 (m, 2H), 4.24-4.08 (m, 1H), 3.22- 3.09 (m,2H), 2.45-2.29 (m, 2H), 1.97-1.89 (m, 2H), 1.52-1.40 (m, 2H), 1.29-1.22(m, 3H), 0.86-0.78 (m, 3H). 232

444.2 ¹H NMR (400 MHz, CD₃OD): δ 5.00-4.89 (m, 1H), 4.81-4.63 (m, 1H),4.52-4.37 (m, 1H), 4.36-4.19 (m, 1H), 2.65-2.46 (m, 3H), 2.28- 2.14 (m,2H), 2.13-1.91 (m, 4H), 1.85-1.70 (m, 1H), 1.39-1.29 (m, 3H). I-82 233

444.2 ¹H NMR (400 MHz, CD₃OD): δ 5.01-4.89 (m, 1H), 4.80-4.62 (m, 1H),4.57-4.29 (m, 2H), 2.74-2.34 (m, 3H), 2.29-1.71 (m, 7H), 1.41- 1.27 (m,3H). I-82 Note: Compounds 230 and 231 were obtained via flash columnchromatography (eluting with gradient H₂O/MeOH = 100:0-0:100). Thecompound obtained from the first elution was named as Compound 230 andthe compound obtained from the second elution was named as Compound 231.

Compounds 242, 266-2693-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohex-2-en-1-D-1-ol,optically pure diastereoisomers

(A)3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluoro-cyclohex-2-en-1-one

Compound 242 was prepared according to the procedure of Step A ofCompounds 95 and 96, using Compound 295 and corresponding reagents. MS(m/z): 434.0 [M+H]+;

¹H NMR (400 MHz, CD₃OD): δ 5.31-5.06 (m, 1H), 5.03-4.90 (m, 2H),3.09-3.00 (br, 1H), 2.90-2.74 (m, 1H), 2.57-2.42 (m, 1H), 2.31-2.12 (m,1H), 1.39-1.31 (m, 6H).

(B)3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluoro-cyclohex-2-en-1-one,optically pure diastereoisomers

Compound 242 was separated by chiral HPLC to give a pair of opticallypure diastereoisomers, Compounds 246 and 247 (Chiral HMPL conditions:Column: AD-H (0.46 cm I.D.×15 cm L); mobile phase:n-heptane/isopropanol=80/20; flow rate: 0.5 mL/min; detectionwavelength: UV 254 nm). The first elution (Compound 246: RT=2.025 min,de %=100%, MS (m/z): 434.0 [M+H]⁺). The second elution (Compound 247:RT=2.083 min, de %=100%, MS (m/z): 434.0 [M+H]⁺).

(C)3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluoro-cyclohex-2-en-1-D-1-ol,optically pure diastereoisomers

Compounds 266 and 267 were prepared according to the procedure ofCompound 1, using Compound 246 and NaBD₄, purified by flash columnchromatography (eluting with PE/EA).

Compound 266: Rf≈0.55, MS (m/z): 437.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):δ 4.93-4.80 (m, 2H), 4.71-4.55 (m, 1H), 2.54-2.40 (m, 2H), 1.97-1.83 (m,2H), 1.30-1.22 (m, 6H).

Compound 267: Rf≈0.50, MS (m/z): 437.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):δ 4.95-4.79 (m, 2H), 4.75-4.57 (m, 1H), 2.68-2.52 (m, 1H), 2.45-2.27 (m,1H), 2.07-1.92 (m, 1H), 1.90-1.75 (m, 1H), 1.31-1.21 (m, 6H).

Compounds 268 and 269 were prepared according to the procedure ofCompound 1, using Compound 247 and NaBD₄, purified by flash columnchromatography (eluting with PE/EA).

Compound 268: Rf≈0.55, MS (m/z): 437.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):δ 4.93-4.80 (m, 2H), 4.71-4.55 (m, 1H), 2.54-2.40 (m, 2H), 1.97-1.83 (m,2H), 1.30-1.22 (m, 6H).

Compound 269: Rf≈0.50, MS (m/z): 437.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):δ 4.95-4.79 (m, 2H), 4.75-4.57 (m, 1H), 2.68-2.52 (m, 1H), 2.45-2.27 (m,1H), 2.07-1.92 (m, 1H), 1.90-1.75 (m, 1H), 1.31-1.21 (m, 6H).

Compound 942,6,6-Trifluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol

(A)(R)-2,6,6-trifluoro-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one(B5)

Under nitrogen atmosphere, to a solution of 1 mol/L LiHMDS in THF (14.85mL, 14.85 mmoL) was added a solution of Compound 123 (1.2 g, 3.30 mmol)in THF (20 mL) dropwise at −78° C. The mixture was stirred at 0° C. for2 hours. Then, to the mixture was added a solution of NFSI (3.12 g, 9.90mmol) in THF drop-wise, then the reaction was warmed to room temperatureslowly and stirred for another 3 hours. After the reaction wascompleted, the mixture was quenched by the addition of saturated NH₄Claqueous solution (30 mL). The organic layer was collected and theaqueous layer was extracted with EtOAc. The organic layers werecombined, dried over Na₂SO₄ and filtered. The filtrate was condensed invacuo and purified by flash column chromatography (eluting with gradientPE/EA=100:0-0:100) to give compound B5 as a white solid (25 mg, yield:1.9%). MS (m/z): 398.1 [M+H]⁺

(B)2,6,6-Trifluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol

Compound 94 was prepared according to the procedure of Compound 39,using compound B5 and corresponding reagents. MS (m/z): 400.2 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 4.97-4.88 (m, 1H), 4.33-4.19 (m, 1H),4.19-4.07 (m, 1H), 2.78-2.61 (m, 1H), 2.59-2.40 (m, 1H), 2.21-2.00 (m,2H), 1.37-1.30 (m, 3H), 1.21-1.12 (m, 6H).

The compounds in the below table were prepared according to theprocedure of Compound 94 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 196

454.1 ¹H NMR (400 MHz, CD₃OD): δ 5.00-4.86 (m, 2H), 4.36-4.17 (m, 1H),2.80-2.65 (m, 1H), 2.58-2.42 (m, 1H), 2.25-2.05 (m, 2H), 1.37- 1.31 (m,6H). I-3 203

442.2 ¹H NMR (400 MHz, CD₃OD): δ 4.37-4.14 (m, 3H), 3.00-2.85 (m, 4H),2.74-2.44 (m, 6H), 2.24-2.02 (m, 2H). I-10 208

440.0 ¹H NMR (400 MHz, CD₃OD): δ 5.01-4.92 (m, 1H), 4.35-4.01 (m, 3H),2.77-2.67 (br, 1H), 2.63-2.46 (m, 1H), 2.33-2.01 (m, 2H), 1.41- 1.32 (m,3H). I-76 209

412.2 ¹H NMR (400 MHz, CD₃OD): δ 4.99-4.90 (m, 1H), 4.31-4.20 (m, 1H),3.25-3.16 (m, 2H), 2.79-2.63 (m, 1H), 2.59-2.44 (m, 1H), 2.23- 2.03 (m,2H), 1.37-1.31 (m, 3H), 1.13-0.99 (m, 1H), 0.53-0.41 (m, 2H), 0.28-0.17(m, 2H). I-78 210

400.0 ¹H NMR (400 MHz, CD₃OD): δ 5.03-4.89 (m, 1H), 4.55-4.37 (m, 1H),4.02-3.77 (m, 2H), 2.81-2.61 (m, 1H), 2.58-2.37 (m, 1H), 2.17- 2.05 (m,1H), 2.04-1.84 (m, 1H), 1.81-1.51 (m, 2H), 1.43-1.31 (m, 3H), 1.05-0.90(m, 3H). I-18 239

448.0 ¹H NMR (400 MHz, CD₃OD): δ 5.02-4.89 (m, 1H), 4.38-4.14 (m, 2H),3.03-2.86 (m, 2H), 2.78-2.44 (m, 4H), 2.30-2.01 (m, 2H), 1.42- 1.30 (m,3H). I-54 245

440.0 ¹H NMR (400 MHz, CD₃OD): δ 5.01-4.92 (m, 1H), 4.35-4.01 (m, 3H),2.77-2.67 (br, 1H), 2.63-2.46 (m, 1H), 2.33-2.01 (m, 2H), 1.41- 1.32 (m,3H). I-76

Compound 2343-(4-((Cyclopropylmethyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol

(A)(R)-3-(4-((cyclopropylmethyl)amino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-one(B7)

The title compound B7 was prepared according to the procedure of Step Aof Compound 94 using compound B6 (prepared according to the procedure ofCompound 1 using Intermediate I-77) and corresponding reagents.

(B)3-(4-((Cyclopropylmethyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol

Compound 234 was prepared according to the procedure of Compound 1,using compound B7 and corresponding reagents. MS (m/z): 412.2 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 4.99-4.90 (m, 1H), 4.31-4.20 (m, 1H),3.25-3.16 (m, 2H), 2.79-2.63 (m, 1H), 2.59-2.44 (m, 1H), 2.23-2.03 (m,2H), 1.37-1.31 (m, 3H), 1.13-0.99 (m, 1H), 0.53-0.41 (m, 2H), 0.28-0.17(m, 2H).

The compounds in the below table were prepared according to theprocedure of Compound 234 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 211

455.1 ¹H NMR (400 MHz, CD₃OD): δ 5.03- 4.87 (m, 2H), 2.82-2.66 (m, 1H),2.62- 2.45 (m, 1H), 2.27-2.02 (m, 2H), 1.40- 1.29 (m, 6H). I-3 235

462.2 ¹H NMR (400 MHz, CD₃OD): δ 5.02- 4.88 (m, 1H), 4.54-4.39 (m, 1H),4.33- 4.17 (m, 1H), 2.79-2.64 (m, 1H), 2.61- 2.44 (m, 2H), 2.29-2.00 (m,6H), 1.90- 1.67 (m, 1H), 1.39-1.31 (m, 3H). I-82 238

398.0 ¹H NMR (400 MHz, CD₃OD): δ 5.05- 4.91 (m, 1H), 4.31-4.20 (m, 1H),2.86- 2.60 (m, 2H), 2.59-2.43 (m, 1H), 2.24- 2.04 (m, 2H), 1.38-1.31 (m,3H), 0.78- 0.66 (m, 2H), 0.57-0.44 (m, 2H). I-16 248

400.0 ¹H NMR (400 MHz, CD₃OD): δ 4.98- 4.90 (m, 1H), 4.32-4.19 (m, 1H),3.38- 3.23 (m, 2H), 2.80-2.61 (m, 1H), 2.60- 2.41 (m, 1H), 2.28-2.02 (m,2H), 1.64- 1.52 (m, 2H), 1.38-1.30 (m, 3H), 0.99- 0.87 (m, 3H). I-18

Compound 2593-(4-((3,3-Difluorocyclobutyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol

(A)(R)-6-(3-((tert-butyldimethylsilyl)oxy)-2-fluorocyclohexa-1,3-dien-1-yl)-N²-(3,3-difluorocyclobutyl)-N⁴-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine(B9)

Under N₂, to a mixture of compound B8 (prepared according to Compound 39using Intermediate I-9: 750 mg, 1.83 mmol) and Et₃N (371 mg, 3.66 mmol)in dry DCM (15 mL) was added a solution of TBSOTf (726 mg, 2.75 mmol) inDCM (5 mL) at 0-5° C. The mixture was stirred for 30 minutes. Then, itwas poured into water and extracted with DCM. The organic layer wascollected, dried over anhydrous Na₂SO₄ condensed under reduced pressuerand purified by flash column chromatography (eluting with PE/EA) to givecompound B9 as a yellow oil (958 mg, yield: 100%). MS (m/z): 524.1[M+H]⁺

(B)3-(4-((3,3-Difluorocyclobutyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohex-2-en-1-one(B10)

Under N₂, a solution of compound B9 (958 mg, 1.83 mmol) in dry MeCN (20mL) was added to the suspension of Selectfluor® (778 mg, 2.20 mmol) indry acetonitrile (20 mL) dropwise at 0-5° C. and stirred for 2 hours.The reaction mixture was poured into water and extracted with EtOAc. Theorganic layer was collected, condensed under reduce pressure andpurified by flash column chromatography (eluting with PE/EA) to givecompound B10 as white solid (512 mg, yield: 66%). MS (m/z): 428.0[M+H]⁺.

(C)(R)-3-(4-((3,3-difluorocyclobutyl)amino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-one(B11)

Under N₂, to a solution of compound B10 (512 mg, 1.12 mmol) in dry THF(10 mL) was added 1M LiHMDS/THF solution (3.47 mL, 3.47 mmol) dropwiseat −78° C. and stirred for 30 minutes. Then to the mixture was addedNFSI (388 mg, 1.23 mmol)/THF solution (10 mL) dropwise at −78° C. andthe reaction was stirred for 2 hours. After the reaction was completed,saturated NH₄Cl aqueous solution was added to quench the reaction. Themixture was extracted with EtOAc. The organic layer was collected,condensed under reduce pressure and purified by flash columnchromatography (eluting with PE/EA) to give compound B11 as yellow solid(230 mg, yield: 46%). MS (m/z): 446.2 [M+H]⁺

(D)3-(4-((3,3-Difluorocyclobutyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol

Compound 259 was prepared according to the procedure of Compound 39,using compound B11 and corresponding reagents. MS (m/z): 448.0 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 4.91-4.81 (s, 1H), 4.26-4.09 (m, 2H),2.92-2.76 (m, 2H), 2.72-2.33 (m, 4H), 2.18-1.96 (m, 2H), 1.30-1.22 (m,3H).

The compounds in the below table were prepared according to theprocedure of Compound 259 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 260

398.0 ¹H NMR (400 MHz, CD₃OD): δ 4.99-4.83 (m, 1H), 4.26-4.09 (m, 1H),2.76-2.53 (m, 2H), 2.51-2.34 (m, 1H), 2.17-1.95 (m, 2H), 1.31- 1.23 (m,3H), 0.69-0.59 (m, 2H), 0.48-0.38 (m, 2H). I-85 261

394.2 ¹H NMR (400 MHz, CD₃OD): δ 4.36-4.09 (m, 3H), 3.02-2.87 (m, 2H),2.79-2.43 (m, 4H), 2.26-2.04 (m, 2H), 1.28-1.15 (m, 6H). I-37 270

440.2 ¹H NMR (400 MHz, CD₃OD): δ 4.92- 4.82 (m, 1H), 4.28-3.90 (m, 3H),2.72-2.38 (m, 2H), 2.20-1.96 (m, 2H), 1.33-1.21 (m, 3H). I-86 271

449.2 ¹H NMR (400 MHz, CD₃OD): δ 8.31-8.20 (m, 1H), 7.63-7.50 (m, 1H),7.25-7.14 (m, 1H), 7.13-7.01 (m, 1H), 4.83-4.68 (m, 1H), 4.52- 4.39 (m,2H), 4.13-3.98 (m, 1H), 2.57-2.18 (m, 2H), 2.08-1.78 (m, 2H), 1.18-1.00(m, 3H). I-87

Compound 2743-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-D-1-ol

(A)3-(4-((3,3-Difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-one(B12)

Under N₂, a mixture of Intermediate I-37 (4.17 g, 15.0 mmol),Intermediate I-88 (4.32 g, 18.0 mmol), Na₂PdCl₄ (221 mg, 0.75 mmol),DTBPPS (402 mg, 1.5 mmol), K₂CO₃ (5.18 g, 37.5 mmol), MeCN (40 mL) andH₂O (10 mL) was stirred at 60° C. for 2 hours. After the reaction wascompleted, the mixture was poured into water and extracted with DCM. Theorganic layer was collected, condensed and purified by flash columnchromatography (eluting with PE/EA) to give Compound B12 as yellow solid(4.98 g, yield: 93%). MS (m/z): 356.1 [M+H]⁺

(B)3-(4-((3,3-Difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohex-2-en-1-one(B13)

The title compound B13 was prepared according to the procedures of StepsA and B of Compound 259, using Compound B12 and corresponding reagents.MS (m/z): 374.1 [M+H]⁺

(C)3-(4-((3,3-Difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-one(B14)

The title compound B14 was prepared according to the procedures of StepsA and B of Compound 259, using compound B13 and corresponding reagents.MS (m/z): 392.0 [M+H]⁺

(D)3-(4-((3,3-Difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-D-1-ol

Compound 274 was prepared according to the procedure of Step B ofCompound 1, using Compound B14, NaBD₄ and corresponding reagents. MS(m/z): 395.1 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 4.33-4.20 (m, 1H), 4.20-4.03 (m, 1H),3.05-2.85 (m, 2H), 2.80-2.41 (m, 4H), 2.29-2.02 (m, 2H), 1.25-1.14 (m,6H).

The compounds in the below table were prepared according to theprocedure of Compound 274 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 275

479.2 ¹H NMR (400 MHz, CD₃OD): δ 8.67- 8.30 (m, 2H), 8.06-7.80 (m, 1H),4.45-4.23 (m, 1H), 2.93-2.75 (m, 1H), 2.69-2.50 (m, 1H), 2.33-2.06 (m,2H), 1.42-1.20 (m, 9H). I-63 276

480.2 ¹H NMR (400 MHz, CD₃OD): δ 8.67- 8.32 (m, 2H), 8.08-7.80 (m, 1H),2.91-2.75 (m, 1H), 2.69-2.52 (m, 1H), 2.32-2.08 (m, 2H), 1.42-1.26 (m,9H). I-63 277

454.2 ¹H NMR (400 MHz, CD₃OD): δ 5.05- 4.91 (m, 2H), 4.38-4.16 (m, 1H),2.83-2.66 (m, 1H), 2.62-2.45 (m, 1H), 2.29-2.03 (m, 2H), 1.44-1.26 (m,6H). I-89 278

399.2 ¹H NMR (400 MHz, CD₃OD): δ 5.14- 4.92 (m, 1H), 2.88-2.64 (m, 2H),2.59-2.43 (m, 1H), 2.32-1.99 (m, 2H), 1.45-1.28 (m, 3H), 0.82-0.66 (m,2H), 0.58-0.45 (m, 2H). I-85 279

399.0 ¹H NMR (400 MHz, CD₃OD): δ 5.13- 4.93 (m, 1H), 2.90-2.64 (m, 2H),2.61-2.41 (m, 1H), 2.33-1.99 (m, 2H), 1.49-1.24 (m, 3H), 0.86-0.67 (m,2H), 0.62-0.46 (m, 2H). I-16 281

436.2 ¹H NMR (400 MHz, CD₃OD): δ 7.22- 6.87 (m, 1H), 5.10-4.91 (m, 2H),4.49-4.21 (m, 1H), 2.90-2.54 (m, 2H), 2.34-1.98 (m, 2H), 1.50-1.20 (m,6H). I-3 282

437.2 ¹H NMR (400 MHz, CD₃OD): δ 7.22- 6.87 (m, 1H), 5.10-4.91 (m, 2H),2.90-2.54 (m, 2H), 2.34-1.98 (m, 2H), 1.50-1.20 (m, 6H). I-3 283

454.0 ¹H NMR (400 MHz, CD₃OD): δ 5.05- 4.90 (m, 2H), 4.40-4.19 (m, 1H),2.84-2.66 (m, 1H), 2.62-2.45 (m, 1H), 2.30-2.03 (m, 2H), 1.42-1.27 (m,6H). I-32 293

430.2 ¹H NMR (400 MHz, CD₃OD): δ 5.09- 4.91 (m, 1H), 4.34-4.21 (m, 1H),2.82-2.68 (m, 1H), 2.61-2.46 (m, 1H), 2.28-2.03 (m, 2H), 1.39-1.34 (m,3H), 1.29-1.26 (m, 9H). I-90 294

430.2 ¹H NMR (400 MHz, CD₃OD): δ 5.09- 4.91 (m, 1H), 4.34-4.21 (m, 1H),2.82-2.68 (m, 1H), 2.61-2.46 (m, 1H), 2.28-2.03 (m, 2H), 1.39-1.34 (m,3H), 1.29-1.26 (m, 9H). I-91 296

452.1 ¹H NMR (400 MHz, CD₃OD): δ 5.01- 4.88 (m, 2H), 3.07-2.09 (m, 4H),1.39-1.31 (m, 6H). I-3 298

437.1 ¹H NMR (400 MHz, CD₃OD): δ 8.77- 8.34 (m, 2H), 8.01-7.69 (m, 1H),4.47-4.17 (m, 1H), 3.81 (s, 3H), 2.89- 2.73 (m, 1H), 2.67-2.52 (m, 1H),2.30-2.06 (m, 2H). I-92

Compound 2972,6,6-Trifluoro-3-(4-(methoxyamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol

(A)(R)-3-(4-chloro-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluoro-cyclohex-2-en-1-one(B16)

The title compound B16 was prepared according to the procedure of StepsB and C of Compound 274, using Intermediate A4 and correspondingreagents. MS (m/z): 375.1 [M+H]⁺

(B)(R)-2,6,6-trifluoro-3-(4-(methoxyamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one(B17)

The title compound B17 was prepared according to the procedure ofCompound 190, using Compound B16 and corresponding reagents. MS (m/z):386.1 [M+H]⁺

(C)2,6,6-Trifluoro-3-(4-(methoxyamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol

Compound 297 was prepared according to the procedure of Step B ofCompound 1, using compound B17 and corresponding reagents. MS (m/z):388.2 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 5.04-4.92 (m, 1H), 4.34-4.20 (m, 1H),3.81-3.66 (m, 3H), 2.80-2.64 (m, 1H), 2.59-2.44 (m, 1H), 2.31-2.04 (m,2H), 1.41-1.32 (m, 3H).

Compound 2803-(4-Amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluoro-cyclohex-2-en-1-ol

(A)(R)-2-fluoro-3-(4-((4-methoxyphenyl)amino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one(B18)

The title compound B18 was prepared according to the procedure ofCompound 1, using Intermediate I-105 and corresponding reagents. MS(m/z): 440.2 [M+H]⁺

(B)(R)-3-(4-amino-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-one(B19)

A mixture of Compound B18 (1.4 g, 3.19 mmol) in TFA (10 mL) was stirredat reflux for 2 hours. The solvent was removed under vacuo. The residuewas dissolved in EtOAc and washed with saturated NaHCO₃ aqueoussolution. The organic layer was collected, condensed under reducedpressure to give title compound B19 as yellow solid (800 mg, yield 79%),which was used for the next step without purification.

(C)3-(4-Amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol

Compound 280 was prepared according to the procedure of Compound 274,using Compound B19 and corresponding reagents. MS (m/z): 358.1 [M+H]⁺;

¹H NMR (400 MHz, CD₃OD): δ 5.00-4.92 (m, 1H), 4.38-4.18 (m, 1H),2.80-2.61 (m, 1H), 2.61-2.44 (m, 1H), 2.31-2.10 (m, 2H), 1.50-1.23 (m,3H).

Compound 2843-(4,6-Diamino-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol

(A)3-(4,6-Bis((3,5-dimethoxybenzyl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one(B20)

The title compound B20 was prepared according to the procedure ofCompound 1, using Intermediate I-106 and corresponding reagents. MS(m/z): 542.1 [M+H]⁺

(B) 3-(4,6-Diamino-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one (B21)

The title compound B21 was prepared according to the procedure of Step Bof Compound 280, using compound B20 and corresponding reagents. MS(m/z): 224.0 [M+H]⁺

(C)3-(4,6-Bis((tert-butyldimethylsilyl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-one(B22)

The title compound B22 was prepared according to the procedure of StepsB and C of Compound 274, using compound B21 and corresponding reagents.MS (m/z): 488.1 [M+H]⁺

(D)3-(4,6-Diamino-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-one(B23)

A solution of Compound B22 (410 mg, 0.84 mmol) in concentrated HClaqueous solution (1 mL) and MeOH (5 mL) was stirred at room temperaturefor 30 minutes. The mixture was diluted with EtOAc and adjusted to pH=8with saturated NaHCO₃ aqueous solution. The organic layer was collected,concentrated to dryness under vacuo and purified by flash columnchromatography (eluting with MeOH and water) to give the title compoundB23 as white solid (150 mg, yield: 69%). MS (m/z): 260.0 [M+H]⁺

(E) 3-(4,6-Diamino-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol

Compound 284 was prepared according to the procedure of Step B ofCompound 1, using Compound B23 and corresponding reagents. MS (m/z):262.0 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 4.33-4.20 (m, 1H), 2.73-2.60 (m, 1H),2.56-2.43 (m, 1H), 2.29-2.04 (m, 2H).

Compound 993-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2-fluoro-cyclohex-2-en-1-ol

(A)3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2-fluoro-cyclohex-2-en-1-one(B24)

To a sealed tube was added3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one(prepared according to the procedure of Compound 1 using IntermediateI-3, 700 mg, 1.69 mmol), NCS (224 mg, 1.69 mmol), TsOH.H₂O (321 mg, 1.69mmol) and MeCN (10 mL) in sequence. The mixture was heated to 80° C. andstirred for 16 hours. After the reaction was completed, the mixture wascooled to room temperature, condensed and purified by flash columnchromatography (eluting with gradient PE/EA=100:0-0:100) to give thetitle compound B24 as white solid (320 mg, yield 42.2%). MS (m/z):450.1, 452.1 [M+H]⁺

(B)3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2-fluoro-cyclohex-2-en-1-ol

Compound 99 was prepared according to the procedure of Compound 39 usingCompound B24 and corresponding reagents. MS (m/z): 452.1 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 5.02-4.90 (m, 2H), 4.40-4.33 (m, 1H),4.27-4.19 (m, 1H), 2.80-2.66 (m, 1H), 2.52-2.38 (m, 1H), 2.13-1.97 (m,2H), 1.36-1.30 (m, 6H).

Compound 122(R)-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one

To a flask were added Intermediate I-2 (500 mg, 1.76 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (391mg, 1.76 mmol), Cs₂CO₃ (1144 mg, 3.52 mmol), Pd(PPh₃)₄ (101 mg, 0.09mmol), 1,4-dioxane (20 mL) and water (4 mL). The mixture was stirred at80° C. for 2 hours under nitrogen atmosphere. After the reaction wascompleted, the mixture was cooled to room temperature, condensed andpurified by flash column chromatography (eluting with PE/EA) to give thetitle compound as a white solid (350 mg, yield 57.9%). MS (m/z): 344.1[M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 7.00 (s, 1H), 5.05-4.86 (m, 1H), 4.26-4.04(m, 1H), 2.87-2.74 (m, 2H), 2.48-2.41 (m, 2H), 2.11-2.02 (m, 2H),1.39-1.32 (m, 3H), 1.23-1.17 (m, 6H).

The compounds in the below table were prepared according to theprocedure of Compound 122 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 123

362.1 ¹H NMR (400 MHz, CD₃OD): δ 5.01- 4.90 (m, 1H), 4.22-4.10 (m, 1H),2.89- 2.77 (m, 2H), 2.64-2.55 (m, 2H), 2.12- 2.02 (m, 2H), 1.39-1.32 (m,3H), 1.23- 1.17 (m, 6H). I-2 295

416.2 ¹H NMR (400 MHz, CD₃OD): δ 5.00- 4.88 (m, 2H), 2.91-2.78 (m, 2H),2.62- 2.53 (m, 2H), 2.11-2.00 (m, 2H), 1.40- 1.30 (m, 6H). I-3

Compound 1243-(4-(Isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol

To a flask were added Compound 122 (250 mg, 0.73 mmol), CeCl₃.7H₂O (353mg, 0.95 mmol) and EtOH (10 mL). The mixture was cooled to 0° C., NaBH₄(36 mg, 0.95 mmol) was added and the reaction was stirred at 0° C. for 2hours. After the reaction was completed, the mixture was quenched by theaddition of saturated NH₄Cl aqueous solution (3 mL) and water (20 mL)and extracted with EtOAc. The organic layer was collected, condensed andpurified by flash column chromatography (eluting with PE/EA) to give thetitle compound as a white solid (210 mg, yield: 83.3%). MS (m/z): 346.0[M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 7.19-6.92 (m, 1H), 5.10-4.87 (m, 1H),4.37-4.26 (m, 1H), 4.25-4.07 (m, 1H), 2.51-2.30 (m, 2H), 2.01-1.82 (m,2H), 1.71-1.49 (m, 2H), 1.38-1.30 (m, 3H), 1.23-1.12 (m, 6H).

The compounds in the below table were prepared according to theprocedure of Compound 124 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 125

332.0 ¹H NMR (400 MHz, CD₃OD): δ 6.88- 6.70 (m, 1H), 5.07-4.87 (m, 2H),4.23- 4.08 (m, 1H), 2.90-2.77 (m, 1H), 2.63- 2.49 (m, 1H), 2.43-2.30 (m,1H), 1.85- 1.69 (m, 1H), 1.39-1.31 (m, 3H), 1.22- 1.17 (m, 6H). I-2 126

400.0 ¹H NMR (400 MHz, CD₃OD): δ 7.23- 7.01 (m, 1H), 5.08-4.87 (m, 2H),4.37- 4.27 (m, 1H), 2.49-2.35 (m, 2H), 1.98- 1.82 (m, 2H), 1.68-1.53 (m,2H), 1.39- 1.32 (m, 6H). I-3 127

388.1 ¹H NMR (400 MHz, CD₃OD): δ 7.22- 6.93 (m, 1H), 4.36-4.19 (m, 3H),2.97- 2.87 (m, 4H), 2.69-2.50 (m, 4H), 2.45- 2.34 (m, 2H), 1.97-1.80 (m,2H), 1.67- 1.51 (m, 2H). I-10 128

358.1 ¹H NMR (400 MHz, CD₃OD): δ 7.26- 6.90 (m, 1H), 5.10-4.92 (m, 1H),4.60- 4.26 (m, 2H), 2.56-2.23 (m, 4H), 2.11- 1.81 (m, 4H), 1.79-1.49 (m,4H), 1.42- 1.28 (m, 3H). I-15 129

344.1 ¹H NMR (400 MHz, CD₃OD): δ 7.27- 6.85 (m, 1H), 5.17-4.95 (m, 1H),4.45- 4.20 (m, 1H), 2.84-2.63 (m, 1H), 2.53- 2.27 (m, 2H), 2.00-1.82 (m,2H), 1.74- 1.51 (m, 2H), 1.43-1.29 (m, 3H), 0.84- 0.67 (m, 2H),0.58-0.46 (m, 2H). I-16 130

372.1 ¹H NMR (400 MHz, CD₃OD): δ 7.22- 6.89 (m, 1H), 5.09-4.92 (m, 1H),4.41- 4.18 (m, 2H), 2.54-2.31 (m, 2H), 2.09- 1.82 (m, 4H), 1.80-1.69 (m,2H), 1.67- 1.44 (m, 6H), 1.40-1.31 (m, 3H). I-12 131

376.1 ¹H NMR (400 MHz, CD₃OD): δ 7.24- 6.95 (m, 1H), 5.12-4.90 (m, 1H),4.43- 4.25 (m, 1H), 3.53-3.37 (m, 2H), 2.47- 2.33 (m, 2H), 2.01-1.81 (m,2H), 1.69- 1.52 (m, 2H), 1.38-1.33 (m, 3H), 1.19 (s, 6H). I-7 132

362.1 ¹H NMR (400 MHz, CD₃OD): δ 7.23- 6.91 (m, 1H), 5.12-4.91 (m, 1H),4.43- 4.25 (m, 1H), 3.65-3.46 (m, 4H), 3.36 (s, 3H), 2.53-2.32 (m, 2H),2.01-1.83 (m, 2H), 1.69-1.52 (m, 2H), 1.40-1.31 (m, 3H). I-17 133

346.1 ¹H NMR (400 MHz, CD₃OD): δ 7.02- 6.87 (m, 1H), 5.11-4.90 (m, 1H),4.40- 4.23 (m, 1H), 3.40-3.30 (m, 2H), 2.55- 2.28 (m, 2H), 1.98-1.81 (m,2H), 1.68- 1.53 (m, 4H), 1.39-1.31 (m, 3H), 0.97- 0.89 (m, 3H). I-18 134

360.1 ¹H NMR (400 MHz, CD₃OD): δ 7.23- 6.90 (m, 1H), 5.14-4.89 (m, 1H),4.45- 4.21 (m, 1H), 3.25-3.07 (m, 2H), 2.50- 2.33 (m, 2H), 1.97-1.80 (m,3H), 1.74- 1.51 (m, 2H), 1.38-1.31 (m, 3H), 0.95- 0.89 (m, 6H). I-13 135

332.1 ¹H NMR (400 MHz, CD₃OD): δ 7.28- 6.88 (m, 1H), 5.14-4.93 (m, 1H),4.40- 4.22 (m, 1H), 3.48-3.35 (m, 2H), 2.57- 2.27 (m, 2H), 1.98-1.83 (m,2H), 1.70- 1.52 (m, 2H), 1.40-1.31 (m, 3H), 1.20- 1.13 (m, 3H). I-19 136

386.1 ¹H NMR (400 MHz, CD₃OD): δ 7.22- 6.92 (m, 1H), 5.11-4.88 (m, 1H),4.41- 4.26 (m, 1H), 3.95-3.72 (m, 1H), 2.53- 2.31 (m, 2H), 2.08-1.86 (m,4H), 1.79- 1.70 (m, 2H), 1.68-1.53 (m, 3H), 1.41- 1.20 (m, 8H). I-20 137

374.1 ¹H NMR (400 MHz, CD₃OD): δ 7.31- 7.215 (m, 1H), 5.09-4.95 (m, 1H),4.39- 4.30 (m, 1H), 3.16-2.81 (m, 1H), 2.51- 2.37 (m, 2H), 2.01-1.84 (m,2H), 1.71- 1.51 (m, 2H), 1.40-1.34 (m, 3H), 1.22- 1.11 (m, 6H). I-4

Compound 138(R)-6-(3,3-difluorocyclohex-1-en-1-yl)-N²-isopropyl-N⁴-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

To a sealed tube were added Compound 122 (100 mg, 0.29 mmol), DAST (1mL), BAST (1 mL) and DCM (10 mL). The mixture was stirred at 80° C. for48 hours. After the reaction was completed, the mixture was cooled toroom temperature, condensed and purified by flash column chromatography(eluting with PE/EA) to give the title compound as a white solid (40 mg,yield: 38.1%). MS (m/z): 366.1 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 7.00-6.82 (m, 1H), 5.05-4.88 (m, 1H),4.27-4.05 (m, 1H), 2.59-2.47 (m, 2H), 2.14-2.00 (m, 2H), 1.91-1.83 (m,2H), 1.39-1.32 (m, 3H), 1.22-1.17 (m, 6H).

Compound 139 in the below table was prepared according to the procedureof Compounds 138 using the corresponding intermediates and reagentsunder appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 139

394.0 ¹H NMR (400 MHz, CD₃OD): δ 7.12- 6.83 (m, 1H), 5.07-4.92 (m, 1H),4.64- 4.41 (m, 1H), 4.03-3.88 (m, 2H), 3.87- 3.76 (m, 1H), 3.72-3.60 (m,1H), 2.64- 2.46 (m, 2H), 2.34-2.18 (m, 1H), 2.13- 2.00 (m, 2H),1.95-1.82 (m, 3H), 1.42- 1.30 (m, 3H). I-8

Compound 1406-(3-Methoxycyclohex-1-en-1-yl)-N²,N⁴-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

A mixture of Compound 126 (100 mg, 0.25 mmol) and Ag₂O (115 mg, 0.5mmol) in CH₃I (4 mL) was stirred at reflux for 16 hours. After thereaction was completed, the mixture was cooled to room temperature,condensed and purified by flash column chromatography (eluting withPE/EA) to give the title compound as a white solid (60 mg, yield:58.3%). MS (m/z): 414.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): δ 7.27-7.08 (m,1H), 5.05-4.87 (m, 2H), 4.03-3.91 (m, 1H), 3.42 (s, 3H), 2.51-2.34 (m,2H), 1.98-1.80 (m, 2H), 1.69-1.56 (m, 2H), 1.38-1.29 (m, 6H).

Compound 1416-(3-(Dimethylamino)cyclohex-1-en-1-yl)-N²,N⁴-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

To a solution of Compound 126 (50 mg, 0.125 mmol) in dry DCM (3 mL) wasadded SOCl₂ (16 mg, 0.137 mmol) under ice bath cooling ° C., and themixture was stirred in ice bath for 30 minutes. Then, the solution wascharged into a sealed tube, dimethylamine hydrochloride (20 mg, 0.25mmol) was added, and the mixture was stirred at reflux overnight. Afterthe reaction was completed, the mixture was cooled to room temperatureand partitioned between EtOAc and water. The organic layer wascollected, condensed and purified by flash column chromatography(eluting with PE/EA) to give the title compound as a white solid (10 mg,yield: 18.9%). MS (m/z): 427.0 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 7.27-7.11 (m, 1H), 5.06-4.89 (m, 2H),3.58-3.44 (m, 1H), 2.64-2.53 (m, 1H), 2.44-2.38 (m, 6H), 2.38-2.25 (m,1H), 2.05-1.92 (m, 2H), 1.66-1.53 (m, 2H), 1.39-1.31 (m, 6H).

Compound 142 in the below table was prepared according to the procedureof Compound 141 using the corresponding intermediates and reagents underappropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 142

413.1 ¹H NMR (400 MHz, CD₃OD): δ 7.26- 7.06 (m, 1H), 5.08-4.91 (m, 2H),3.89- 3.73 (m, 1H), 2.74-2.66 (m, 3H), 2.63- 2.44 (m, 2H), 2.19-2.07(m,1H), 2.02- 1.92 (m, 1H), 1.76-1.57(m, 2H), 1.38- 1.33 (m, 6H). Comp. 126

Compound 1433-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-1-(trifluoromethyl)-cyclohex-2-en-1-ol

To a solution of3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one(prepared according to the procedure of Compound 122 using correspondingintermediates and reagents, 100 mg, 0.25 mmol) andtrimethyl(trifluoromethyl)silane (142 mg, 1.25 mmol) in dry THF (10 mL)was added TBAF (1M, 1.25 mL) under ice bath cooling ° C. The mixture wasstirred at reflux for 2 hours, quenched by the addition of saturatedNH₄Cl aqueous solution and extracted with EtOAc. The organic layer wascollected, condensed and purified by flash column chromatography(eluting with PE/EA) to give the title compound as a white solid (10 mg,yield: 8.6%). MS (m/z): 468.0 [M+H]⁺;

¹H NMR (400 MHz, CD₃OD): δ 7.10 (s, 1H), 5.05-4.88 (m, 2H), 2.81-2.63(m, 1H), 2.35-2.21 (m, 1H), 1.92-1.77 (m, 4H), 1.39-1.31 (m, 6H).

Compound 1443-(4-(Isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-3-en-1-ol

(A)(R)—N²-isopropyl-6-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)-N⁴-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine(B25)

Under nitrogen atmosphere, to a flask were added Intermediate I-2 (320mg, 1.13 mmol),4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)-1,3,2-dioxaborolane(300 mg, 1.13 mmol), Cs₂CO₃ (734 mg, 2.26 mmol), Pd(PPh₃)₄ (69 mg, 0.06mmol), 1,4-dioxane (10 mL) and water (2 mL). The mixture was stirred at80° C. for 2 hours. After the reaction was completed, the mixture wascooled to room temperature, condensed and purified by flash columnchromatography (eluting with PE/EA) to give the title compound B25 aswhite solid.

(B)(R)-3-(4-(Isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-3-en-1-one(B26)

To the solution of Compound B25 in dry DCM (3 mL) was added TFA (3 mL)and the mixture was stirred overnight at room temperature. After thereaction was completed, the reaction was quenched by the addition ofsaturated NaHCO₃ aqueous solution and extracted with EtOAc. The organiclayer was collected, condensed and purified by flash columnchromatography (eluting with PE/EA) to give the title compound B26 asyellow solid (200 mg, yield: 51.5%). MS (m/z): 344.3 [M+H]⁺

(C)3-(4-(Isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-3-en-1-ol

Compound 144 was prepared according to the procedure of Compound 124using Compound B26 and corresponding reagents. MS (m/z): 346.3 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 7.27-6.96 (m, 1H), 5.08-4.89 (m, 1H),4.28-4.07 (m, 1H), 4.02-3.83 (m, 1H), 2.91-2.72 (m, 1H), 2.47-2.20 (m,3H), 1.93-1.80 (m, 1H), 1.65-1.53 (m, 1H), 1.38-1.28 (m, 3H), 1.24-1.13(m, 6H).

Compound 145 in the below table was prepared according to the procedureof Compound 144 using the corresponding intermediates and reagents underappropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 145

346.3 ¹H NMR (400 MHz, CD₃OD): δ 7.1-6.90 (m, 1H), 5.04-4.88 (m, 1H),4.25-4.07 (m, 1H), 3.97-3.85 (m, 1H), 2.74-2.60 (m, 1H), 2.57-2.48 (m,1H), 2.46-2.33 (m, 1H), 2.21-2.09 (m, 1H), 1.97-1.87 (m, 1H), 1.70-1.58(m, 1H), 1.36-1.29 (m, 3H), 1.21-1.14 (m, 6H). I-2

Compound 1522-Fluoro-3-(4-(((R)-1-phenylethyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol

To a sealed tube was added Intermediate I-1 (50 mg, 0.15 mmol),(R)-1-phenylethan-1-amine (36 mg, 0.30 mmol), DIEA (77 mg, 0.60 mmol)and 1,4-dioxane (3 mL) in sequence. The mixture was stirred at 100° C.for 2 hours. After the reaction was completed, the mixture was cooled toroom temperature, condensed and purified by flash column chromatography(eluting with PE/EA) to give the title compound as white solid (15 mg,yield: 23.4%). MS (m/z): 426.3 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 7.35-7.15 (m, 5H), 5.22-4.60 (m, 2H),4.33-4.21 (m, 1H), 2.62-2.23 (m, 2H), 1.89-1.73 (m, 3H), 1.67-1.58 (m,1H), 1.50-1.44 (m, 3H), 1.34-1.28 (m, 2H), 1.16-1.07 (m, 1H).

The compounds in the below table were prepared according to theprocedure of Compound 152 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 153

394.1 ¹H NMR (400 MHz, CD₃OD): δ 7.21- 6.96 (m, 1H), 5.09-4.88 (m, 1H),4.39- 4.13 (m, 2H), 2.99-2.87 (m, 2H), 2.71- 2.50 (m, 2H), 2.47-2.32 (m,2H), 1.99- 1.81 (m, 2H), 1.67-1.52 (m, 2H), 1.39- 1.31 (m, 3H). I-25 154

386.1 ¹H NMR (400 MHz, CD₃OD): δ 7.26- 7.03 (m, 1H), 5.07-4.90 (m, 1H),4.38- 4.26 (m, 1H), 4.21-4.02 (m, 2H), 2.49- 2.33 (m, 2H), 1.97-1.82 (m,2H), 1.67- 1.52 (m, 2H), 1.39-1.31 (m, 3H). I-25 155

360.1 ¹H NMR (400 MHz, CD₃OD): δ 7.21- 6.89 (m, 1H), 5.07-4.87 (m, 1H),4.36- 4.24 (m, 1H), 2.48-2.33 (m, 2H), 1.97- 1.83 (m, 2H), 1.68-1.52 (m,2H), 1.43 (s, 9H), 1.38-1.32 (m, 3H). I-25 156

358.1 ¹H NMR (400 MHz, CD₃OD): δ 7.25- 6.90 (m, 1H), 5.13-4.93 (m, 1H),4.38- 4.23 (m, 1H), 2.54-2.31 (m, 2H), 1.97- 1.81 (m, 2H), 1.69-1.51 (m,2H), 1.42- 1.31 (m, 6H), 0.80-0.72 (m, 2H), 0.66- 0.58 (m, 2H). I-25 157

426.4 ¹H NMR (400 MHz, CD₃OD): δ 7.40- 7.15 (m, 5H), 5.23-4.62 (m, 2H),4.34- 4.18 (m, 1H), 2.62-2.24 (m, 2H), 1.88- 1.60 (m, 4H), 1.53-1.44 (m,3H), 1.35- 1.29 (m, 2H), 1.18-1.07 (m, 1H). I-1 158

390.1 ¹H NMR (400 MHz, CD₃OD): δ 4.99- 4.88 (m, 1H), 4.33-4.22 (m, 1H),3.61- 3.40 (m, 1H), 2.65- 2.47 (m, 1H), 2.43- 2.25 (m, 1H), 1.91-1.72(m, 3H), 1.70- 1.59 (m, 1H), 1.36-1.31 (m, 3H), 1.27- 1.21 (m, 3H),1.03-0.86 (m, 1H), 0.56- 0.30 (m, 3H), 0.26-0.15 (m, 1H). I-1 159

416.3 ¹H NMR (400 MHz, CD₃OD): δ 4.97- 4.88 (m, 1H), 4.35-4.13 (m, 2H),2.60- 2.47 (m, 1H), 2.44-2.26 (m, 3H), 2.10- 2.02 (m, 2H), 1.97-1.76 (m,9H), 1.70- 1.60 (m, 1H), 1.38-1.29 (m, 3H). I-1 160

452.3 ¹H NMR (400 MHz, CD₃OD): δ 4.97- 4.89 (s, 1H), 4.43-4.22 (m, 2H),2.68- 2.43 (m, 7H), 2.37-2.25 (m, 1H), 2.121- 2.06 (m, 2H), 1.91-1.73(m, 3H), 1.73- 1.58 (m, 1H), 1.37-1.29 (m, 3H). I-1 161

418.3 ¹H NMR (400 MHz, CD₃OD): δ 4.97- 4.88 (m, 1H), 4.78-4.71 (m, 2H),4.64- 4.55 (m, 2H), 4.37-4.14 (m, 2H), 2.70- 2.48 (m, 3H), 2.38-2.12 (m,3H), 1.90- 1.61 (m, 4H), 1.38-1.29 (m, 3H). I-1 162

362.3 ¹H NMR (400 MHz, CD₃OD): δ 5.10- 4.89 (m, 1H), 4.33-4.20 (m, 1H),2.79- 2.67 (m, 1H), 2.64-2.48 (m, 1H), 2.40- 2.22 (m, 1H), 1.89-1.72 (m,3H), 1.70- 1.59 (br, 1H), 1.40-1.31 (m, 3H), 0.77- 0.67 (m, 2H),0.55-0.48 (m, 2H). I-1 163

392.3 ¹H NMR (400 MHz, CD₃OD): δ 4.98- 4.89 (m, 1H), 4.33-4.22 (m, 1H),4.00- 3.86 (m, 1H), 2.62-2.47 (m, 1H), 2.41- 2.23 (m, 1H), 1.89-1.72 (m,4H), 1.71- 1.60 (m, 1H), 1.38-1.30 (m, 3H), 1.15- 1.07 (m, 3H),0.96-0.88 (m, 6H). I-1 164

378.3 ¹H NMR (400 MHz, CD₃OD): δ 4.97- 4.90 (m, 1H), 4.34-4.22 (m, 1H),4.03- 3.91 (m, 1H), 2.63-2.48 (m, 1H), 2.40- 2.24 (m, 1H), 1.90-1.73 (m,3H), 1.69- 1.61 (m, 1H), 1.58-1.47 (m, 2H), 1.39- 1.30 (m, 3H),1.19-1.11 (m, 3H), 0.97- 0.88 (m, 3H). I-1 165

378.3 ¹H NMR (400 MHz, CD₃OD): δ 4.97- 4.90 (m, 1H), 4.34-4.22 (m, 1H),4.03- 3.91 (m, 1H), 2.63-2.48 (m, 1H), 2.40- 2.24 (m, 1H), 1.90-1.73 (m,3H), 1.69- 1.61 (m, 1H), 1.58-1.47 (m, 2H), 1.39- 1.30 (m, 3H),1.19-1.11 (m, 3H), 0.97- 0.88 (m, 3H). I-1 166

426.3 ¹H NMR (400 MHz,CD₃OD): δ 5.02- 4.95 (m, 1H), 4.78-4.57 (m, 1H),4.41- 4.22 (m, 1H), 2.57-2.52 (m, 1H), 2.43- 2.31 (m, 1H), 2.27-2.05 (m,3H), 1.95- 1.62 (m, 7H), 1.43-1.31 (m, 3H). I-1 167

392.4 ¹H NMR (400 MHz, CD₃OD): δ 5.00- 4.93 (m, 1H), 4.36-4.23 (m, 1H),4.04- 3.90 (m, 1H), 2.64-2.50 (m, 1H), 2.40- 2.27 (m, 1H), 1.90-1.63 (m,5H), 1.40- 1.32 (m, 3H), 1.18-1.09 (m, 3H), 0.98- 0.88 (m, 6H). I-1 168

389.3 ¹H NMR (400 MHz, CD₃OD): δ 4.99- 4.93 (m, 1H), 4.42-4.25 (m, 2H),2.88- 2.71 (m, 2H), 2.66-2.52 (m, 1H), 2.44- 2.28 (m, 1H), 1.92-1.83 (m,2H), 1.82- 1.73 (m, 1H), 1.71-1.63 (m, 1H), 1.42- 1.31 (m, 6H). I-1 169

382.2 ¹H NMR (400 MHz, CD₃OD): δ 5.01- 4.92 (m, 1H), 4.51-4.26 (m, 4H),2.64- 2.49 (m, 1H), 2.39-2.25 (m, 1H), 1.90- 1.61 (m, 4H), 1.40-1.31 (m,3H), 1.27- 1.19 (m, 3H). I-1 170

382.3 ¹H NMR (400 MHz, CD₃OD): δ 5.01- 4.92 (m, 1H), 4.51-4.26 (m, 4H),2.64- 2.49 (m, 1H), 2.39-2.25 (m, 1H), 1.90- 1.61 (m, 4H), 1.40-1.31 (m,3H), 1.27- 1.19 (m, 3H). I-1 171

426.3 ¹H NMR (400 MHz, CD₃OD): δ 4.99- 4.91 (m, 1H), 4.34-4.24 (m, 1H),3.67- 3.44 (m, 2H), 3.19-3.03 (m, 1H), 2.60- 2.30 (m, 4H), 1.95-1.74 (m,4H), 1.70- 1.62 (m, 1H), 1.58-1.49 (m, 1H), 1.39- 1.33 (m, 3H). I-1 172

394.3 ¹H NMR (400 MHz, CD₃OD): δ 5.02- 4.93 (m, 1H), 4.33-4.26 (m, 1H),2.63- 2.55 (m, 1H), 2.34-2.28 (m, 1H), 1.90- 1.76 (m, 3H), 1.71-1.62 (m,1H), 1.38- 1.35 (m, 3H), 1.28 (s, 9H). I-1 173

405.2 ¹H NMR (400 MHz, CD₃OD): δ 5.01- 4.90 (m, 1H), 4.58-4.43 (m, 1H),4.35- 4.25 (m, 1H), 3.00-2.84 (m, 1H), 2.71- 2.42 (m, 4H), 2.40-2.21 (m,5H), 1.89- 1.58 (m, 5H), 1.40-1.28 (m, 3H). I-61 174

400.2 ¹H NMR (400 MHz, CD₃OD): δ 6.07- 5.70 (m, 1H), 5.01-4.88 (m, 1H),4.52- 4.35 (m, 1H), 4.33-4.23 (m, 1H), 2.65- 2.51 (m, 1H), 2.44-2.25 (m,1H), 1.89- 1.61 (m, 4H), 1.38-1.30 (m, 3H), 1.28- 1.21 (m, 3H). I-61 175

414.2 ¹H NMR (400 MHz, CD₃OD): δ 5.03- 4.89 (m, 1H), 4.69-4.51 (m, 1H),4.35- 4.22 (m, 1H), 2.68-2.50 (m, 1H), 2.41- 2.25 (m, 1H), 1.90-1.73 (m,3H), 1.68- 1.50 (m, 4H), 1.38-1.31 (m, 3H), 1.28- 1.22 (m, 3H). I-61 176

408.1 ¹H NMR (400 MHz, CD₃OD): δ 7.27- 6.94 (m, 1H), 5.10-4.87 (m, 1H),4.57- 4.38 (m, 1H), 4.36-4.25 (m, 1H), 2.62- 2.48 (m, 1H), 2.47-2.32 (m,2H), 2.28- 2.15 (m, 2H), 2.13-1.97 (m, 2H), 1.96- 1.72 (m, 3H), 1.66-1.50 (m, 2H), 1.39- 1.31 (m, 3H). I-26 177

408.1 ¹H NMR (400 MHz, CD₃OD): δ 7.27- 6.94 (m, 1H), 5.10-4.87 (m, 1H),4.57- 4.38 (m, 1H), 4.36-4.25 (m, 1H), 2.62- 2.48 (m, 1H), 2.47-2.32 (m,2H), 2.28- 2.15 (m, 2H), 2.13-1.97 (m, 2H), 1.96- 1.72 (m, 3H), 1.66-1.50 (m, 2H), 1.39- 1.31 (m, 3H). I-27 178

360.0 ¹H NMR (400MHz, CD₃OD): δ 7.17- 6.98 (m, 1H), 5.18-4.90 (m, 2H),4.90- 4.86 (m, 2H), 4.66-4.59 (m, 2H), 4.35- 4.26 (m, 1H), 2.46-2.35 (m,2H), 1.97- 1.81 (m, 2H), 1.67-1.52 (m, 2H), 1.35- 1.30 (m, 3H). I-27 179

374 ¹H NMR (400 MHz, CD₃OD): δ 7.23- 6.95 (m, 1H), 5.08-4.90 (m, 1H),4.61- 4.44 (m, 1H), 4.35-4.25 (m, 1H), 4.00- 3.89 (m, 2H), 3.85-3.76 (m,1H), 3.70- 3.59 (m, 1H), 2.48-2.35 (m, 2H), 2.29- 2.18 (m, 1H),1.96-1.83 (m, 3H), 1.68- 1.52 (m, 2H), 1.37-1.31 (m, 3H). I-27 180

374 ¹H NMR (400 MHz, CD₃OD): δ 7.23- 6.95 (m, 1H), 5.08-4.90 (m, 1H),4.61- 4.44 (m, 1H), 4.35-4.25 (m, 1H), 4.00- 3.89 (m, 2H), 3.85-3.76 (m,1H), 3.70- 3.59 (m, 1H), 2.48-2.35 (m, 2H), 2.29- 2.18 (m, 1H),1.96-1.83 (m, 3H), 1.68- 1.52 (m, 2H), 1.37-1.31 (m, 3H). I-27 181

422.1 ¹H NMR (400 MHz, CD₃OD): δ 7.23- 6.93 (m, 1H), 5.13-4.88 (m, 1H),4.39- 4.27 (m, 1H), 4.14-3.91 (m, 1H), 2.53- 2.35 (m, 2H), 2.14-1.81 (m,8H), 1.73- 1.51 (m, 4H), 1.40-1.30 (m, 3H). I-27 182

388.2 ¹H NMR (400 MHz, CD₃OD): δ 7.24- 6.90 (m, 1H), 5.10-4.88 (m, 1H),4.39- 4.27 (m, 1H), 4.23-4.08 (m, 2H), 2.46- 2.35 (m, 2H), 2.07-1.97 (m,1H), 1.95- 1.80 (m, 4H), 1.70-1.52 (m, 5H), 1.37- 1.31 (m, 3H). I-27 183

376.3 ¹H NMR (400 MHz, CD₃OD): δ 7.20- 6.93 (m, 1H), 5.07-4.89 (m, 1H),4.37- 4.19 (m, 2H), 3.48-3.41 (m, 1H), 3.38- 3.32 (m, 4H), 2.45-2.34 (m,2H), 1.96- 1.81 (m, 2H), 1.67-1.53 (m, 2H), 1.37- 1.31 (m, 3H),1.20-1.15 (m, 3H). I-27 184

362.2 ¹H NMR (400 MHz, CD₃OD): δ 7.19- 6.91 (m, 1H), 5.06-4.90 (m, 1H),4.35- 4.07 (m, 2H), 3.63-3.48 (m, 2H), 2.47- 2.33 (m, 2H), 1.96-1.81 (m,2H), 1.67- 1.52 (m, 2H), 1.36-1.31 (m, 3H), 1.22- 1.16 (m, 3H). I-27

Compound 1866-(Cyclohex-1-en-1-yl)-N²,N⁴-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

Under nitrogen atmosphere, to a flask was added Intermediate I-3 (150mg, 0.44 mmol), cyclohex-1-en-1-ylboronic acid (85 mg, 0.66 mmol),Cs₂CO₃ (290 mg, 0.88 mmol), Pd(PPh₃)₄ (26 mg, 0.022 mmol), 1,4-dioxane(10 mL) and water (2 mL) in sequence. The mixture was stirred at 100° C.for 16 hours. After the reaction was completed, the mixture was cooledto room temperature, condensed and purified by flash columnchromatography (eluting with PE/EA) to give the title compound as whitesolid (154 mg, yield: 90.4%). MS (m/z): 384.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ 7.84-7.60 (m, 2H), 7.18 (s, 1H), 5.07-4.76(m, 2H), 2.40-2.28 (m, 2H), 2.25-2.16 (m, 2H), 1.68-1.52 (m, 4H),1.34-1.25 (m, 6H).

The compounds in the below table were prepared according to theprocedure of Compound 186 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 187

300.2 ¹H NMR (400 MHz, CD₃OD): δ 7.20- 6.87 (m, 1H), 3.27-3.16 (m, 4H),2.45-2.34 (m, 2H), 2.26-2.18 (m, 2H), 1.74-1.60 (m, 4H), 1.12-1.00 (m,2H), 0.53-0.39 (m, 4H), 0.29-0.16 (m, 4H). I-6 188

360.1 ¹H NMR (400 MHz, CD₃OD): δ 7.41- 6.99 (m, 1H), 5.11-4.88 (m, 1H),3.60-3.34 (m, 2H), 2.55-2.35 (m, 2H), 2.29-2.15 (m, 2H), 1.81-1.57 (m,4H), 1.40-1.30 (m, 3H), 1.19 (s, 6H). I-7 189

316.1 ¹H NMR (400 MHz, CD₃OD): δ 6.96- 6.78 (m, 1H), 5.06-4.87 (m, 1H),4.25-4.07 (m, 1H), 2.72-2.62 (m, 2H), 2.56-2.49 (m, 2H), 2.03-1.93 (m,2H), 1.38-1.30 (m, 3H), 1.22-1.15 (m, 6H). I-2

Compound 190(R)-6-(cyclohex-1-en-1-yl)-N²-isopropyl-N⁴-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

A mixture of Intermediate I-22 (85 mg, 0.33 mmol),(R)-1,1,1-trifluoropropan-2-amine hydrochloride (201 mg, 1.34 mmol) andDIEA (0.47 mL, 2.69 mmol) in 1,4-dioxane (3 mL) was stirred undermicrowave at 150° C. for 3 hours. After the reaction was completed, themixture was cooled to room temperature, condensed and purified by flashcolumn chromatography (eluting with PE/EA) to give the title compound asyellow solid (18 mg, yield 14%). MS (m/z): 330.1 [M+H]⁺

¹H NMR (400 MHz, CD₃OD): δ 7.32-6.94 (m, 1H), 4.66-4.52 (7, 1H),4.32-4.02 (m, 1H), 2.52-2.33 (m, 2H), 2.29-2.16 (i, 2H), 1.79-1.60 (i,4H), 1.40-1.29 (i, 3H), 1.24-1.14 (i, 6H).

The compounds in the below table were prepared according to theprocedure of Compound 190 using the corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 191

328.2 ¹H NMR (400 MHz, CD₃OD): δ 7.19- 6.85 (m, 1H), 3.60-3.40 (m, 2H),2.46- 2.29 (m, 2H), 2.25-2.16 (m, 2H), 1.73- 1.60 (m, 4H), 1.23 (d, J =6.6 Hz, 6H), 0.97-0.85 (m, 2H), 0.53-0.30 (m, 6H), 0.23-0.15 (m, 2H).I-23 192

342.1 ¹H NMR (400 MHz, CD₃OD): δ 7.30- 7.02 (m, 1H), 5.08-4.90 (m, 1H),3.28- 3.16 (m, 2H), 2.50-2.34 (m, 2H), 2.28- 2.18 (m, 2H), 1.79-1.59 (m,4H), 1.40- 1.31 (m, 3H), 1.15-1.01 (m, 1H), 0.56- 0.44 (m, 2H),0.30-0.19 (m, 2H). I-24 193

260.1 ¹H NMR (400 MHz, CD₃OD): δ 7.25- 6.82 (m, 1H), 3.28-3.13 (m, 2H),2.89 (s, 3H), 2.47-2.33 (m, 2H), 2.27-2.17 (m, 2H), 1.75-1.60 (m, 4H),1.14-0.99 (m, 1H), 0.53-0.42 (m, 2H), 0.31-0.17 (m, 2H). I-24 194

288.2 ¹H NMR (400 MHz, CD₃OD): δ 7.24- 6.85 (m, 1H), 4.27-4.06 (m, 1H),3.28- 3.17 (m, 2H), 2.45-2.35 (m, 2H), 2.26- 2.19 (m, 2H), 1.75-1.61 (m,4H), 1.19 (d, J = 6.5 Hz, 6H), 1.12-1.01 (m, 1H), 0.53-0.43 (m, 2H),0.29-0.18 (m, 2H). I-24 195

318.2 ¹H NMR (400 MHz, CD₃OD): δ 7.26- 6.89 (m, 1H), 3.45-3.35 (m, 2H),3.27- 3.16 (m, 2H), 2.45-2.35 (m, 2H), 2.26- 2.19 (m, 2H), 1.75-1.61 (m,4H), 1.20 (s, 6H), 1.10-1.02 (m, 1H), 0.52-0.43 (m, 2H), 0.26-0.19 (m,2H). I-24

Compounds 206 and 2073-(5-Fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-2-yl)cyclohex-2-en-1-oland3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclohex-2-en-1-ol

(A) A mixture of2-chloro-5-fluoro-N⁴,N⁶-bis((R)-1,1,1-trifluoropropan-2-yl)pyrimidine-4,6-diamineand6-chloro-5-fluoro-N²,N⁴-bis((R)-1,1,1-trifluoropropan-2-yl)pyrimidine-2,4-diamine

Under nitrogen atmosphere, a mixture of2,4,6-trichloro-5-fluoropyrimidine (1.12 g, 5.6 mmol),(R)-1,1,1-trifluoropropan-2-amine hydrochloride (2.51 g, 16.8 mmol),DIEA (4.22 g, 56 mmol) and N-methylpyrrolidone (5 mL) was stirred undermicrowave at 200° C. for 1 hour. After cooled to room temperature, themixture was directly injected into RP-C18 column and purified by flashcolumn chromatography (eluting with gradient water/MeOH=100:0-0:100) togive the product as white solid (80 mg, yield 4.2%). MS (m/z): 354.9[M+H]⁺

(B) A mixture of3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-2-yl)cyclohex-2-en-1-one and3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclohex-2-en-1-one

Under nitrogen atmosphere, a mixture of the product obtained in step (A)(80 mg, 0.23 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (50mg, 0.23 mmol), Cs₂CO₃ (150 mg, 0.46 mmol), 1,4-dioxane (5 mL) and water(1.5 mL) was stirred under microwave at 130° C. for 40 minutes. Aftercooled to room temperature, the mixture was condensed and purified byflash column chromatography (eluting with gradient PE/EA=100:0-0:100) togive the product as white solid (60 mg, yield: 63.2%). MS (m/z): 415.0[M+H]⁺

(C)3-(5-Fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-2-yl)cyclohex-2-en-1-ol and3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclohex-2-en-1-ol

Compounds 206 and 207 were prepared according to the procedure ofCompound 124 using the mixture of3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-2-yl)cyclohex-2-en-1-one and3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl) cyclohex-2-en-1-one obtained in step(B) and corresponding reagents, and purified by flash columnchromatography (eluting with gradient PE/EA=100:0-0:100).

Compound 206, MS (m/z): 417.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ6.97-6.89 (m, 1H), 5.21-5.03 (m, 2H), 4.38-4.26 (m, 1H), 2.55-2.34 (m,2H), 1.96-1.82 (m, 2H), 1.68-1.52 (m, 2H), 1.42-1.32 (m, 6H).

Compound 207, MS (m/z): 417.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ6.47-6.40 (m, 1H), 5.10-4.97 (m, 1H), 4.82-4.72 (m, 1H), 4.35-4.26 (m,1H), 2.50-2.30 (m, 2H), 1.99-1.85 (m, 2H), 1.71-1.56 (m, 2H), 1.38 (d,J=7.1 Hz, 3H), 1.32 (d, J=7.0 Hz, 3H).

The compounds in the below table were prepared according to theprocedure described above, using corresponding intermediates andreagents under appropriate conditions that will be recognized by POSITA:

MS Inter- Comp. Structure (M + H)⁺ ¹H NMR mediate 212

451.2 ¹H NMR (400 MHz, CD₃OD): δ 8.54-8.35 (m, 2H), 7.98-7.78 (m, 1H),4.37-4.24 (m, 1H), 4.10-3.94 (m, 2H), 2.89-2.72 (m, 1H), 2.66- 2.52 (m,1H), 2.33-2.05 (m, 2H), 1.33-1.24 (m, 3H). I-93 213

477.2 ¹H NMR (400 MHz, CD₃OD): δ 8.50-8.31 (m, 2H), 8.00-7.88 (m, 1H),4.41-4.24 (m, 1H), 3.78 (d, J = 7.2 Hz, 2H), 2.90-2.73 (m, 1H), 2.66-2.49 (m, 1H), 2.32-2.05 (m, 2H), 1.26-1.09 (m, 1H), 0.62-0.51 (m, 2H),0.35-0.25 (m, 2H). I-94 214

480.0 ¹H NMR (400 MHz, CD₃OD): δ 8.92-8.76 (m, 1H), 8.73-8.64 (m, 1H),4.40- 4.26 (m, 1H), 2.93-2.77 (m, 1H), 2.71-2.55 (m, 1H), 2.34- 2.07 (m,2H), 1.31 (s, 9H). I-95 215

429.2 ¹H NMR (400 MHz, CD₃OD): δ 8.05-7.88 (m, 2H), 7.47-7.43 (m, 1H),4.34-4.30 (m, 1H), 2.85-2.77 (m, 1H), 2.65-2.55 (m, 1H), 2.31- 2.06 (m,2H), 1.32 (s, 9H). I-65 216

445.0 ¹H NMR (400 MHz, CD₃OD): δ 8.31 (s, 1H), 8.13-8.02 (m, 1H),7.64-7.47 (m, 1H), 4.38-4.23 (m, 1H), 2.89- 2.71 (m, 1H), 2.66-2.50 (m,1H), 2.32-2.03 (m, 2H), 1.32 (s, 9H). I-96 217

465.2 ¹H NMR (400 MHz, CD₃OD): δ 8.61-8.28 (m, 2H), 8.07-7.76 (m, 1H),4.42-4.16 (m, 1H), 4.03-3.82 (m, 2H), 2.88-2.72 (m, 1H), 2.67- 2.50 (m,1H), 2.31-2.06 (m, 2H), 1.80-1.63 (m, 2H), 1.10-0.90 (m, 3H). I-97 218

497.2 ¹H NMR (400 MHz, CD₃OD): δ 8.61-8.26 (m, 2H), 7.91-7.74 (m, 1H),4.45-4.21 (m, 1H), 3.98-3.77 (m, 4H), 2.90-2.75 (m, 1H), 2.65- 2.41 (m,3H), 2.30-2.05 (m, 2H). I-98 220

501.1 ¹H NMR (400 MHz, CD₃OD): δ 8.77-7.63 (m, 2H), 7.68 (s, 1H), 4.39-4.18 (m, 1H), 3.27-3.16 (m, 1H), 2.89-2.45 (m, 2H), 2.33- 2.02 (m, 2H),1.17-0.98 (m, 2H), 0.60- 0.47 (m, 2H), 0.44-0.27 (m, 6H). I-99 221

483.2 ¹H NMR (400 MHz, CD₃OD): δ 8.50-8.37 (m, 2H), 7.88-7.80 (m, 1H),4.60-4.40 (m, 4H), 4.34-4.27 (m, 1H), 2.85-2.75 (m, 1H), 2.65- 2.55 (m,1H), 2.31-2.05 (m, 2H). I-100 243

434.0 ¹H NMR (400 MHz, CD₃OD): δ 5.03-4.86 (m, 1H), 4.49-4.34 (m, 4H),4.30-4.20 (m, 1H), 2.75-2.65 (m, 1H), 2.55-2.45 (m, 1H), 2.27- 2.02 (m,2H), 1.45-1.33 (m, 3H). I-101 244

400.0 ¹H NMR (400 MHz, CD₃OD): δ 5.01-4.90 (br, 1H), 4.37-4.20 (m, 1H),4.19-4.03 (m, 1H), 2.85-2.39 (m, 2H), 2.32-2.02 (m, 2H), 1.43- 1.29 (m,3H), 1.23-1.09 (m, 6H). I-2 299

434.0 ¹H NMR (400 MHz, CD₃OD): δ 5.04-4.86 (m, 1H), 4.50-4.34 (m, 4H),4.31-4.20 (m, 1H), 2.78-2.65 (m, 1H), 2.59-2.44 (m, 1H), 2.29- 1.98 (m,2H), 1.41-1.31 (m, 3H). I-102 300

545.1 ¹H NMR (400 MHz, CD₃OD): δ 8.60-8.47 (m, 1H), 8.43-8.38 (m, 1H),7.86-7.70 (m, 1H), 4.38-4.23 (m, 1H), 4.01 -3.66 (m, 4H), 2.89- 2.73 (m,1H), 2.69-2.51 (m, 1H), 2.41-2.06 (m, 4H). I-103 301

533.1 ¹H NMR (400 MHz, CD₃OD): δ 8.51-8.43 (m, 1H), 8.42-8.38 (m, 1H),7.91-7.84 (m, 1H), 4.40-4.29 (m, 1H), 4.24-4.12 (m, 4H), 2.93- 2.77 (m,1H), 2.69-2.55 (m, 1H), 2.36-2.06 (m, 2H). I-104

Compounds 197 and 1983-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol,optically pure diastereoisomers

The Compound 196 was resolved by chiral HPLC to provide a pair ofoptically pure diastereoisomers, Compounds 197 and 198 (Chiral HPLCconditions: Preparation instrument: Shimadzu LC-10AD vp; Column: DaicelAD-H (250 mm*30 mm, Sum); mobile phase: n-heptane/isopropanol=90/10;flow rate: 40 mL/min; column temperature: 40° C.). The first eluent(RT=4.203 min) was concentrated and purified by flash columnchromatography (eluting with gradient PE/EA=100:0-0:100) to give acompound named as Compound 197, de %=99.27%, MS (m/z): 454.1 [M+1]⁺. Thesecond eluent (RT=5.906 min) was concentrated and purified by flashcolumn chromatography (eluting with gradient PE/EA=100:0-0:100) to givea compound named as Compound 198, de %=97.82%, MS (m/z): 454.2 [M+1]⁺.

Compound 197: ¹H NMR (400 MHz, CD₃OD): δ 5.00-4.86 (m, 2H), 4.36-4.17(m, 1H), 2.80-2.65 (m, 1H), 2.58-2.42 (m, 1H), 2.25-2.05 (m, 2H),1.37-1.31 (m, 6H).

Compound 198: ¹H NMR (400 MHz, CD₃OD): δ 5.00-4.86 (m, 2H), 4.36-4.17(m, 1H), 2.80-2.65 (m, 1H), 2.58-2.42 (m, 1H), 2.25-2.05 (m, 2H),1.37-1.31 (m, 6H).

The compounds in the below table were prepared according to theprocedure of Compounds 197 and 198 using the corresponding compounds andunder appropriate HPLC conditions (flow rate: 0.5 mL/min; detectionwavelength: UV 254 nm):

Comp. for MS RT Chiral HPLC separa- Comp. Structure (M + H)⁺ ¹H NMR(min) Purity Condition tion 100

364.1 ¹H NMR (400 MHz, CD₃OD): δ 5.00- 4.89 (m, 1H), 4.33-4.24 (m, 1H),4.21- 4.06 (m, 1H), 2.63-2.47 (m, 1H), 2.41- 2.47 (br, 1H), 1.93-1.71(m, 3H), 1.70- 1.61 (m, 1H), 1.40-1.30 (m, 3H), 1.21- 1.15 (m, 6H).1.230 ee% = 100% Column: OJ-H (0.46 cm I.D. × 15 cm L); Mobile phase:n-heptane/ isopropanol (0.1% Et₂NH) = 90/10 1 101 364.1 ¹H NMR (400 MHz,CD₃OD): δ 5.01- 1.316 ee% = 4.90 (m, 1H), 4.34-4.24 (m, 1H), 4.20- 100%4.06 (m, 1H), 2.65-2.48 (m, 1H), 2.43- 2.23 (m, 1H), 1.92-1.72 (m,3H),1.68- 1.59 (m, 1H), 1.40-1.31 (m, 3H), 1.21- 1.14 (m, 6H). 102

418.0 ¹H NMR (400 MHz, CD₃OD): δ 5.03- 4.88 (m, 2H), 4.34-4.25 (m, 1H),2.68- 2.51 (m, 1H), 2.41-2.26 (m, 1H), 1.90- 1.74 (m, 3H), 1.70-1.58 (m,1H), 1.37- 1.31 (m, 6H) 1.899 de% = 100% Column: AD-H (0.46 cm I.D. × 15cm L); Mobile phase: n-heptane/ isopropanol (0.1% Et₂NH) = 80/20 2 103418.1 ¹H NMR (400 MHz, CD₃OD): δ 5.02- 2.263 de% = 4.87 (m, 2H),4.34-4.24 (m, 1H), 2.64- 100% 2.50 (m, 1H), 2.45-2.32 (m, 1H), 1.91-1.71 (m, 3H), 1.69-1.71 (m, 1H), 1.38- 1.30 (m, 6H). 104

406.3 ¹H NMR (400 MHz, CD₃OD): δ 4.37- 4.22 (m, 3H), 3.02-2.86 (m, 4H),2.73- 2.50 (m, 5H), 2.41-2.25 (m, 1H), 1.91- 1.72 (m, 3H), 1.72-1.62 (m,1H). 3.608 ee% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobilephase: n-heptane/ isopropanol (0.1% EtNH) = 70/30 5 105 406.3 ¹H NMR(400 MHz, CD₃OD): δ 4.37- 3.871 ee% = 4.22 (m, 3H), 3.02-2.86 (m, 4H),2.73- 100% 2.50 (m, 5H), 2.41-2.25 (m, 1H), 1.91- 1.72 (m, 3H),1.72-1.62 (m, 1H). 106

432.1 ¹H NMR (400 MHz, CD₃OD): δ 5.02- 4.89 (m, 2H), 4.53-4.41 (m, 1H),2.77- 2.62 (m, 1H), 2.40-2.27 (m, 1H), 2.02- 1.83 (m, 3H), 1.74-1.61 (m,3H), 1.39- 1.32 (m, 6H) 10.540 de% = 97.79% Column: AS-H (0.46 cm I.D. ×15 cm L); Mobile phase: n-heptane/ isopropanol = 90/10 19 107 432.2 ¹HNMR (400 MHz, CD₃OD): δ 5.02- 18.120 de% = 4.89 (m, 2H), 4.53-4.41 (m,1H), 2.77- 97.84% 2.62 (m, 1H), 2.40-2.27 (m, 1H), 2.02- 1.83 (m, 3H),1.74-1.61 (m, 3H), 1.39- 1.32 (m, 6H) 108

407.1 ¹H NMR (400 MHz, CD₃OD): δ 4.38- 4.15 (m, 2H), 3.05-2.85 (m, 4H),2.72- 2.48 (m, 5H), 2.40-2.26 (m, 1H), 1.90- 1.61 (m, 4H) 4.596 de% =99.8% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/isopropanol = 70/30 109 407.1 ¹H NMR (400 MHz, CD₃OD): δ 4.38- 4.897 de%= 4.15 (m, 2H), 3.05-2.85 (m, 4H), 2.72- 99.32% 2.48 (m, 5H), 2.40-2.26(m, 1H), 1.90- 1.61 (m, 4H). 110

419.1 ¹H NMR (400 MHz, CD₃OD): δ 5.02- 4.87 (m, 2H), 2.68-2.51 (m, 1H),2.44- 2.28 (m, 1H), 1.92-1.63 (m, 4H), 1.42- 1.30 (m, 6H) 10.090 de% =100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/isopropanol = 90/10 18 111 419.1 ¹H NMR (400 MHz, CD₃OD): δ 5.02- 16.800de% = 4.87 (m, 2H), 2.68-2.51 (m, 1H), 2.44- 100% 2.28 (m, 1H),1.92-1.63 (m, 4H), 1.42- 1.30 (m, 6H) 112

421.1 ¹H NMR (400 MHz, CD₃OD): δ 5.00- 4.87 (m, 2H), 2.63-2.53 (m, 1H),2.37- 2.26 (m, 1H), 1.81-1.69 (m, 1H), 1.67- 1.60 (m, 1H), 1.37-1.31 (m,6H) 5.500 de% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobilephase: n-heptane/ isopropanol = 80/20 83 113 421.1 ¹H NMR (400 MHz,CD₃OD): δ 5.00- 7.420 de% = 4.87 (m, 2H), 2.63-2.53 (m, 1H), 2.37-97.54% 2.26 (m, 1H), 1.81-1.69 (m, 1H), 1.67- 1.60 (m, 1H), 1.37-1.31(m, 6H) 114

415.1 ¹H NMR (400 MHz, CD₃OD): δ 4.98- 4.89 (m, 1H), 4.35-4.13 (m, 1H),3.02- 2.81 (m, 2H), 2.75-2.46 (m, 3H), 2.44- 2.24 (m, 1H), 1.82-1.71 (m,1H), 1.69- 1.58 (m, 1H), 1.38-1.28 (m, 3H) 5.960 de% = 100% Column: AD-H(0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 80/2090 115 415.1 ¹H NMR (400 MHz, CD₃OD): δ 4.98- 7.800 de% = 4.89 (m, 1H),4.35-4.13 (m, 1H), 3.02- 98.30% 2.81 (m, 2H), 2.75-2.46 (m, 3H), 2.44-2.24 (m, 1H), 1.82-1.71 (m, 1H), 1.69- 1.58 (m, 1H), 1.38-1.28 (m, 3H)116

409.1 ¹H NMR (400 MHz, CD₃OD): δ 4.36- 4.14 (m, 2H), 2.98-2.85 (m, 4H),2.67- 2.46 (m, 5H), 2.39-2.22 (m, 1H), 1.82- 1.71 (m, 1H), 1.68-1.57 (m,1H) 10.170 de% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobilephase: n-heptane/ isopropanol = 80/20 91 117 409.1 ¹H NMR (400 MHz,CD₃OD): δ 4.36- 13.590 de% = 4.14 (m, 2H), 2.98-2.85 (m, 4H), 2.67-99.16% 2.46 (m, 5H), 2.39-2.22 (m, 1H), 1.82- 1.71 (m, 1H), 1.68-1.57(m, 1H) 118

364.1 ¹H NMR (400 MHz, CD₃OD): δ 5.00- 4.89 (m, 1H), 4.36-4.25 (m, 1H),4.19- 4.08 (m, 1H), 2.68-2.50 (m, 1H), 2.40- 2.24 (m, 1H), 1.96-1.57 (m,4H), 1.41- 1.29 (m, 3H), 1.23-1.12 (m, 6H) 1.334 de% = 97.56% Column:AS-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol =90/10 33 119 364.1 ¹H NMR (400 MHz, CD₃OD): δ 5.01- 1.403 de% = 4.89 (m,1H), 4.32-4.25 (m, 1H), 4.20- 100% 4.07 (m, 1H), 2.64-2.48 (m, 1H),2.42- 2.26 (m, 1H), 1.93-1.59 (m, 4H), 1.38- 1.31 (m, 3H), 1.22-1.15 (m,6H) 120

412.0 ¹H NMR (400 MHz, CD₃OD): δ 5.05- 4.89 (m, 1H), 4.41-4.13 (m, 2H),3.08- 2.80 (m, 2H), 2.78-2.24 (m, 4H), 2.01- 1.60 (m, 4H), 1.47-1.24 (m,3H) 2.589 de% = 100% Column: OJ-H (0.46 cm I.D. × 25 cm L); Mobilephase: n-heptane/ isopropanol (0.1% Et₂NH) = 90/10 31 121 412.0 ¹H NMR(400 MHz, CD₃OD): δ 5.07- 3.189 de% = 4.88 (m, 1H), 4.39-4.13 (m, 2H),3.06- 100% 2.83 (m, 2H), 2.77-2.23 (m, 4H), 1.95- 1.60 (m, 4H),1.45-1.28 (m, 3H) 146

346.1 ¹H NMR (400 MHz, CD₃OD): δ 7.21- 6.90 (m, 1H), 5.03-4.92 (m, 1H),4.36- 4.26 (m, 1H), 4.22-4.07 (m, 1H), 2.48- 2.34 (m, 2H), 1.96-1.83 (m,2H), 1.66- 1.54 (m, 2H), 1.37-1.31 (m, 3H), 1.26- 1.13 (m, 6H) 1.526 de%= 100% Column: AS-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/isopropanol = 80/20 124 147 346.1 ¹H NMR (400 MHz, CD₃OD): δ 7.18- 1.995de% = 6.93 (m, 1H), 5.06-4.91 (m, 1H), 4.37- 99.774% 4.25 (m, 1H),4.24-4.06 (m, 1H), 2.51- 2.28 (m, 2H), 1.98-1.79 (m, 2H), 1.69 - 1.49(m, 2H), 1.38-1.30 (m, 3H), 1.22- 1.15 (m, 6H) 148

400.1 ¹H NMR (400 MHz, CD₃OD): δ 7.22- 7.03 (m, 1H), 5.06-4.87 (m, 2H),4.36- 4.26 (m, 1H), 2.50-2.34 (m, 2H), 1.99- 1.81 (m, 2H), 1.68-1.50 (m,2H), 1.38- 1.31 (m, 6H) 1.169 de% = 100% Column: AS-H (0.46 cm I.D. × 15cm L); Mobile phase: n-heptane/ isopropanol (0.1% Et₂NH) = 80/20 126 149400.1 ¹H NMR (400 MHz, CD₃OD): δ 7.22- 2.443 de% = 7.03 (m, 1H),5.06-4.87 (m, 2H), 4.36- 100% 4.26 (m, 1H), 2.50-2.34 (m, 2H), 1.99-1.81 (m, 2H), 1.68-1.50 (m, 2H), 1.38- 1.31 (m, 6H) 150

388.1 ¹H NMR (400 MHz, CD₃OD): δ 7.22- 6.93 (m, 1H), 4.36-4.19 (m, 3H),2.97- 2.87 (m, 4H), 2.69-2.50 (m, 4H), 2.45- 2.34 (m, 2H), 1.97-1.80 (m,2H), 1.67- 1.51 (m, 2H) 2.492 ee% = 100% Column: AS-H (0.46 cm I.D. × 15cm L); Mobile phase: n-heptane/ isopropanol = 70/30 127 151 388.1 ¹H NMR(400 MHz, CD₃OD): δ 7.22- 3.658 ee% = 6.93 (m, 1H), 4.36-4.19 (m, 3H),2.97- 100% 2.87 (m, 4H), 2.69-2.50 (m, 4H), 2.45- 2.34 (m, 2H),1.97-1.80 (m, 2H), 1.67- 1.51 (m, 2H) 222

431.0 ¹H NMR (400 MHz, CD₃OD): δ 8.93- 8.78 (m, 2H), 7.98-7.93 (m, 1H),7.84- 7.77 (m, 1H), 4.37-4.30 (m, 1H), 2.70- 2.61 (m, 1H), 2.48-2.36 (m,1H), 1.92- 1.86 (m, 2H), 1.85-1.76 (m, 1H), 1.73- 1.65 (m, 1H), 1.33 (s,9H) 5.097 ee% = 99.89% Column: IC-H (0.46 cm I.D. x 15 cm L); Mobilephase: n-heptane/ isopropanol = 60/40 34 223 431.0 ¹H NMR (400 MHz,CD₃OD): δ 8.93- 6.651 ee% = 8.75 (m, 2H), 7.98-7.93 (m, 1H), 7.83-97.67% 7.77 (m, 1H), 4.37-4.30 (m, 1H), 2.71- 2.61 (m, 1H), 2.48-2.36(m, 1H), 1.92- 1.86 (m, 2H), 1.85-1.77 (m, 1H), 1.73- 1.66 (m, 1H), 1.33(s, 9H) 236

442.2 ¹H NMR (400 MHz, CD₃OD): δ 4.41- 4.08 (m, 3H), 3.01-2.82 (m, 4H),2.74- 2.43 (m, 6H), 2.25-2.02 (m, 2H) 4.121 ee% = 100% Column: AD-H(0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol (0.1%Et₂NH) = 80/20 203 237 442.2 ¹H NMR (400 MHz, CD₃OD): δ 4.41- 4.453 ee%= 4.08 (m, 3H), 3.01-2.82 (m, 4H), 2.74- 100% 2.43 (m, 6H), 2.25-2.02(m, 2H) 249

455.2 ¹H NMR (400 MHz, CD₃OD): δ 5.03- 4.87 (m, 2H), 2.82-2.66 (m, 1H),2.62- 2.45 (m, 1H), 2.27-2.02 (m, 2H), 1.40- 1.29 (m, 6H) 2.293 de% =100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/isopropanol (0.1% Et₂NH) = 80/20 211 250 455.2 ¹H NMR (400 MHz, CD₃OD):δ 5.03- 2.898 de% = 4.87 (m, 2H), 2.82-2.66 (m, 1H), 2.62- 100% 2.45 (m,1H), 2.27-2.02 (m, 2H), 1.40- 1.29 (m, 6H) 251

398.0 ¹H NMR (400 MHz, CD₃OD): δ 5.14- 4.92 (m, 1H), 4.33-4.19 (m, 1H),2.81- 2.60 (m, 2H), 2.60-2.41 (m, 1H), 2.25- 2.05 (m, 2H), 1.38-1.32 (m,3H), 0.77- 0.69 (m, 2H), 0.55-0.48 (m, 2H) 2.179 de% = 100% Column: OJ-H(0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 90/10238 252 398.0 ¹H NMR (400 MHz, CD₃OD): δ 5.04- 2.465 de% = 4.94 (m, 1H),4.32-4.19 (m, 1H), 2.83- 99.76% 2.61 (m, 2H), 2.58-2.42 (m, 1H), 2.23-2.05 (m, 2H), 1.39-1.32 (m, 3H), 0.77- 0.69 (m, 2H), 0.57-0.47 (m, 2H)253

448.0 ¹H NMR (400 MHz, CD₃OD): δ 5.04- 4.89 (m, 1H), 4.38-4.16 (m, 2H),3.05- 2.85 (m, 2H), 2.81-2.43 (m, 4H), 2.31- 1.96 (m, 2H), 1.42-1.30 (m,3H) 3.225 de% = 100% Column: OJ-H (0.46 cm I.D. × 15 cm L); Mobilephase: n-heptane/ ethanol = 80/20 239 254 448.0 ¹H NMR (400 MHz, CD₃OD):δ 5.05- 3.790 de% = 4.92 (m, 1H), 4.34-4.14 (m, 2H), 3.02- 100% 2.85 (m,2H), 2.80-2.45 (m, 4H), 2.29- 2.01 (m, 2H), 1.43-1.29 (m, 3H) 255

440.0 ¹H NMR (400 MHz, CD₃OD): δ 4.97- 4.83 (m, 1H), 4.29-3.90 (m, 3H),2.77- 2.58 (m, 1H), 2.51-2.37 (m, 1H), 2.26- 1.93 (m, 2H), 1.37-1.20 (m,3H) 3.119 de% = 100% Column: OJ-H (0.46 cm I.D. × 15 cm L); Mobilephase: n-heptane/ isoproanol = 80/20 245 256 440.0 ¹H NMR (400 MHz,CD₃OD): δ 5.03- 3.644 de% = 4.82 (m, 1H), 4.27 -3.84 (m, 3H), 2.75- 100%2.58 (m, 1H), 2.52-2.35 (m 1H), 2.21- 1.95 (m, 2H), 1.39-1.23 (m, 3H)257

400.0 ¹H NMR (400 MHz, CD₃OD): δ 4.90- 4.81 (m, 1H), 4.24-4.11 (m, 1H),3.33- 3.14 (m, 2H), 2.70-2.55 (m, 1H), 2.48- 2.34 (m, 1H), 2.17-2.96 (m,2H), 1.56- 1.44 (m, 2H), 1.29-1.23 (m, 3H), 0.88- 0.80 (m, 3H) 3.436 de%= 99.24% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/isopropanol = 80/20 248 258 400.0 ¹H NMR (400 MHz, CD₃OD): δ 4.90- 4.005de% = 4.83 (m, 1H), 4.25-4.10 (m, 1H), 3.34- 99.74% 3.13 (m, 2H),2.70-2.54 (m, 1H), 2.54- 2.33 (m, 1H), 2.19-1.96 (m, 2H), 1.56- 1.44 (m,2H), 1.29-1.22 (m, 3H), 0.89- 0.81 (m, 3H) 262

447.9 ¹H NMR (400 MHz, CD₃OD): δ 5.04- 4.95 (m, 1H), 4.42-4.14 (m, 2H),3.04- 2.87 (m, 2H), 2.84-2.45 (m, 4H), 2.31- 2.06 (m, 2H), 1.45-1.33 (m,3H) 3.388 de% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobilephase: n-heptane/ isopropanol = 80/20 259 263 448.0 ¹H NMR (400 MHz,CD₃OD): δ 4.92- 3.968 de% = 4.83 (m, 1H), 4.31-4.04 (m, 2H), 2.94-99.48% 2.73 (m, 2H), 2.72-2.34 (m, 4H), 2.18- 1.91 (m, 2H), 1.32-1.21(m, 3H) 264

398.0 ¹H NMR (400 MHz, CD₃OD): δ 5.00- 4.83 (m, 1H), 4.26-4.09 (m, 1H),2.73- 2.53 (m, 2H), 2.53-2.34 (m, 1H), 2.17- 1.94 (m, 2H), 1.31-1.22 (m,3H), 0.70- 0.58 (m, 2H), 0.47-0.39 (m, 2H) 3.524 de% = 99.56% Column:AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol =80/20 260 265 398.0 ¹H NMR (400 MHz, CD₃OD): δ 5.03- 3.737 de% = 4.83(m, 1H), 4.26-4.10 (m, 1H), 2.78- 99.58% 2.54 (m, 2H), 2.52-2.32 (m,1H), 2.19- 1.94 (m, 2H), 1.32-1.22 (m, 3H), 0.71- 0.53 (m, 2H),0.51-0.35 (m, 2H) 272

394.1 ¹H NMR (400 MHz, CD₃OD): δ 4.36- 4.09 (m, 3H), 3.02-2.87 (m, 2H),2.79- 2.43 (m, 4H), 2.26-2.04 (m, 2H), 1.28- 1.15 (m, 6H) 4.176 ee% =100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/isopropanol = 70/30 261 273 394.0 ¹H NMR (400 MHz, CD₃OD): δ 4.36- 4.696ee% = 4.09 (m, 3H), 3.02-2.87 (m, 2H), 2.79- 100% 2.43 (m, 4H),2.26-2.04 (m, 2H), 1.28- 1.15 (m, 6H) 285

479.2 ¹H NMR (400 MHz, CD₃OD): δ 8.67- 8.30 (m, 2H), 8.06-7.80 (m, 1H),4.45- 4.23 (m, 1H), 2.93-2.75 (m, 1H), 2.69- 2.50 (m, 1H), 2.33-2.06 (m,2H), 1.42- 1.20 (m, 9H) 3.399 ee% = 100% Column: AD-H (0.46 cm I.D. × 15cm L); Mobile phase: n-heptane/ isopropanol = 70/30 275 286 479.2 ¹H NMR(400 MHz, CD₃OD): δ 8.67- 4.089 ee% = 8.30 (m, 2H), 8.06-7.80 (m, 1H),4.45- 100% 4.23 (m, 1H), 2.93-2.75 (m, 1H), 2.69- 2.50 (m, 1H),2.33-2.06 (m, 2H), 1.42- 1.20 (m, 9H) 287

480.2 ¹H NMR (400 MHz, CD₃OD): δ 8.67- 8.32 (m, 2H), 8.08-7.80 (m, 1H),2.91- 2.75 (m, 1H), 2.69-2.52 (m, 1H), 2.32- 2.08 (m, 2H), 1.42-1.26 (m,9H) 3.400 ee% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobilephase: n-heptane/ isopropanol = 70/30 276 288 480.2 ¹H NMR (400 MHz,CD₃OD): δ 8.67- 4.086 ee% = 8.32 (m, 2H), 8.08-7.80 (m, 1H), 2.91- 100%2.75 (m, 1H), 2.69-2.52 (m, 1H), 2.32- 2.08 (m, 2H), 1.42-1.26 (m, 9H)289

358.2 ¹H NMR (400 MHz, CD₃OD): δ 5.00- 4.92 (m, 1H), 4.38-4.18 (m, 1H),2.80- 2.61 (m, 1H), 2.61-2.44 (m, 1H), 2.31- 2.10 (m, 2H), 1.50-1.23 (m,3H) 3.506 de% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobilephase: n-heptane/ isopropanol = 80/20 280 290 358.1 ¹H NMR (400 MHz,CD₃OD): δ 5.00- 3.754 de% = 4.92 (m, 1H), 4.38-4.18 (m, 1H), 2.80- 100%2.61 (m, 1H), 2.61-2.44 (m, 1H), 2.31- 2.10 (m, 2H), 1.50-1.23 (m, 3H)291

436.2 ¹H NMR (400 MHz, CD₃OD): δ 7.22- 6.87 (m, 1H), 5.10-4.91 (m, 2H),4.49- 4.21 (m, 1H), 2.90-2.54 (m, 2H), 2.34- 1.98 (m, 2H), 1.50-1.20 (m,6H) 2.376 de% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobilephase: n-heptane/ isopropanol = 80/20 281 292 436.2 ¹H NMR (400 MHz,CD₃OD): δ 7.22- 3.321 de% = 6.87 (m, 1H), 5.10-4.91 (m, 2H), 4.49- 100%4.21 (m, 1H), 2.90-2.54 (m, 2H), 2.34- 1.98 (m, 2H), 1.50-1.20 (m, 6H)

Example 3 Fluorescent Determination of IDH2-R140Q Cell Activity

Materials:

U87MGR140Q cells: U87MG cells were purchased from ATCC cell bank andthen transfected with plasmid containing IDH2-R140Q mutation, andmonoclonal cells stably expressing the R140Q mutation were isolated forexperiments. The cells were cultured in MEM medium containing 10% FBS.

96-well plate a: Beckman Dickinson, Catalog No. 353072;

96-well plate b: Thermo, Catalog No. 249952;

96-well plate c: Greiner, Catalog No. 675076.

Solution Preparation:

Enzyme reaction solution: 1 mM nicotinamide adenine dinucleotide (NAD),0.6 ng/μL D-2-hydroxyglutarate dehydrogenase (D2HGDH), 0.8 U/mLlipoamidase dehydrogenase (Diaphorase) and 60 μM Resazurin in 40 mMTris.HCl pH 8.8 assay buffer.

Standard curve stock solution: The standard of 2-HG sodium salt wasserially diluted in serum-free MEM medium to make a standard curve stocksolution. The final gradient concentrations are: 500 μM, 167 μM, 56 μM,18.5 μM, 6 μM, 2 μM, 0.7 μM, 0.2 μM.

Methods:

100 μL of U87MGR140Q cells were seeded at a density of 6×10⁴/mL per wellin a 96-well plate a. The plate was incubated at 37° C. with 5% CO₂overnight, then 10 μL per well of test compound solution diluted inserum-free MEM (final concentration of test compound: 10 μM, 3.3 μM, 1.1μM, 0.37 μM, 0.12 μM, 0.041 μM, 0.014 μM and 0.005 μM, final DMSOconcentration is 0.5%) or 10 μL of control solution (serum-free MEMmedium containing 0.5% DMSO in final concentration) was added andincubated for 72 hours.

From each well of 96-well plate a, 50 μL of the culture supernatant wastransferred to the corresponding well of 96-well plate b; at the sametime, 50 μL of standard curve stocking solution was added to other wellsof 96-well plate b. Then 10 μl of 360 mM hydrochloric acid was added toall the wells. After shaking and mixing, the plate was placed on ice for10 minutes, and then 10 μl of 420 mM Tris-base was added. After shakingand mixing, the plate was placed on ice for additional 5 minutes. Thenthe plate was centrifuged at 2500 rpm for 10 minutes.

After centrifuging, from each well of 96-well plate b, 20 μL of thesupernatant was transferred to 96-well plate c. An additional 80 μL ofthe enzyme reaction solution was added to each well and incubated at 25°C. for 90 minutes.

Detection:

The plate c was measured on Tecan Infinite F500 Reader instrument at 544nm excitation and 590 nm emission. A standard curve of the fluorescencevalue vs. the corresponding 2-HG concentration was made, and the 2-HGconcentration corresponding to each concentration point of the compoundwas calculated, then the inhibition ratio was calculated, and the datawas analyzed using XLfit5 (ID Business Solutions Limited) software toobtain the IC₅₀ value.

The inhibition ratio was calculated as follows:

Inhibition Ratio (IH %)=(1-2-HG concentration of test compound treatedcells/2-HG concentration of control cells)×100%.

The followings are the activity values of some of the compounds of theinvention determined in this example.

Compound IC₅₀ (μM) 1 0.097 2 0.137 3 0.866 4 0.080 5 0.093 6 0.115 70.087 8 0.216 9 0.571 10 0.113 11 0.284 12 0.199 13 0.373 14 0.230 150.259 16 0.326 17 1.616 18 0.110 19 0.083 20 0.232 21 0.099 22 0.336 230.192 24 0.197 25 0.665 27 0.148 28 0.123 29 0.177 30 0.228 31 0.110 320.080 34 0.145 35 0.591 36 0.181 37 1.911 38 1.619 39 0.164 40 0.106 410.297 42 0.152 43 0.328 44 3.149 47 0.059 49 0.210 50 0.072 51 0.125 520.229 53 0.131 54 0.015 55 0.103 56 0.093 57 2.180 58 0.169 59 0.221 600.590 61 0.170 62 1.343 64 1.628 65 0.152 67 2.374 68 0.435 69 0.173 700.112 71 0.050 72 0.042 73 0.064 74 0.034 75 0.218 78 0.069 79 0.106 800.079 81 0.099 82 0.075 83 0.203 84 0.048 85 0.035 86 0.021 87 0.205 890.057 90 0.065 91 0.058 92 0.143 94 0.131 95 0.043 96 0.675 97 0.052 980.344 99 0.553 100 2.905 101 0.080 102 0.051 103 1.002 104 2.079 1050.040 106 0.106 107 0.554 108 2.226 109 0.057 110 0.070 111 2.257 1120.098 113 2.059 114 1.716 115 0.059 116 2.620 117 0.095 118 0.106 1193.393 120 2.397 121 0.068 122 1.340 124 0.137 125 1.671 126 0.086 1270.064 128 0.092 129 0.171 130 0.067 131 2.798 133 0.174 134 0.100 1350.336 136 0.296 137 1.540 138 0.504 139 2.505 140 2.390 144 2.748 1460.999 147 0.067 148 1.558 149 0.177 150 0.541 151 0.039 152 0.300 1530.099 154 0.202 155 0.319 156 0.657 157 0.141 158 0.278 159 0.205 1600.180 162 0.177 163 0.162 164 0.176 165 0.198 166 0.180 167 0.327 1690.738 170 1.382 171 0.268 172 0.344 174 0.096 175 0.291 176 0.612 1770.046 178 0.934 179 0.598 180 0.531 181 0.177 182 1.231 183 0.507 1843.779 186 0.677 187 0.742 188 5.015 189 1.415 190 0.413 191 0.999 1920.314 196 0.094 197 0.041 198 0.845 199 1.504 200 0.632 201 0.045 2020.383 203 0.098 204 0.209 205 0.803 207 0.564 208 0.102 209 0.078 2100.093 211 0.097 212 0.063 213 0.038 214 0.108 215 0.079 216 0.082 2170.069 218 0.381 219 0.707 220 0.059 221 0.487 222 0.065 224 0.137 2250.036 226 0.361 227 0.048 228 0.417 229 0.383 230 0.658 231 0.037 2320.040 233 0.368 234 0.078 235 0.130 236 0.045 237 1.492 238 0.139 2390.046 240 0.984 241 0.100 242 0.802 243 1.175 244 0.053 245 0.102 2480.093 249 0.072 250 2.473 252 0.050 254 0.025 255 0.078 257 0.056 2590.057 260 0.094 261 0.094 262 0.056 263 1.394 264 0.084 266 0.033 2671.327 268 0.349 269 0.137 270 0.109 272 0.051 273 1.228 274 0.084 2750.062 276 0.081 277 0.156 278 0.148 279 0.170 280 >10 281 0.690 2820.343 283 0.174 285 0.034 286 0.165 287 0.095 288 0.035 291 0.201 2923.456 293 0.637 294 0.425 296 0.423 297 2.660 298 0.620

Example 4 Fluorescent Determination of IDH1-R132H Cell Activity

The 2-HG inhibitory activity of the compounds of the invention inU87MGR132H cells transfected with the IDH1-R132H mutant plasmid wasdetermined according to the method of Example 3.

The followings are the activity values of some of the compounds of theinvention determined in this example.

Compound IC₅₀ (μM) 2 0.365 4 0.750 5 0.869 6 0.670 7 1.503 8 1.221 111.016 13 2.076 14 1.326 15 0.619 18 0.219 19 0.421 21 0.234 24 0.769 310.280 32 0.610 34 >10 39 1.913 40 0.450 41 1.627 47 5.636 51 6.042 522.245 54 1.683 60 >10 61 >10 62 2.703 64 >10 65 >10 67 >10 71 3.05473 >10 74 7.441 75 >10 78 1.407 79 1.296 80 2.695 81 3.571 82 0.181 830.282 84 0.268 85 0.207 87 0.781 89 2.957 94 1.144 95 0.317 96 2.703 970.047 98 0.254 99 0.938 101 1.141 102 0.232 103 2.501 105 0.351 1060.272 107 1.751 109 0.279 110 0.160 118 2.141 119 >10 121 0.186 1240.658 126 0.289 127 0.203 130 0.733 134 2.472 136 1.342 147 0.372 1490.693 151 0.256 152 2.008 153 0.447 155 2.245 157 4.350 158 1.520 1592.717 163 0.809 166 1.347 167 3.171 169 9.464 170 6.933 171 1.575 1740.343 175 0.495 177 0.094 181 0.476 196 0.210 197 0.120 198 1.893199 >10 200 >10 201 0.109 202 1.101 203 0.733 204 >10 205 >10 207 1.510208 1.499 209 1.763 210 4.338 211 0.175 212 >10 213 >10 214 >10 215 >10216 8.519 217 >10 218 >10 219 3.232 220 2.878 221 >10 222 >10 224 4.650225 0.917 226 5.123 227 0.081 228 0.705 229 >10 230 >10 231 1.528 2320.070 233 0.628 234 1.763 235 0.246 236 0.252 238 7.355 239 0.344240 >10 241 2.060 242 3.523 243 >10 244 1.082 245 1.499 248 4.338 2490.134 250 2.480 252 2.621 254 0.262 255 0.715 257 1.380 259 0.213260 >10 261 2.231 262 0.182 263 3.513 264 >10 266 0.043 267 3.566 2680.939 269 0.296 270 2.853 272 2.086 273 >10 274 3.284 275 8.017 2768.367 277 1.030 278 >10 279 9.426 280 >10 281 0.455 282 0.444 283 1.319285 3.587 286 >10 287 >10 288 2.695 291 0.179 292 3.639 293 >10 2949.184 296 1.135 297 >10 298 >10

Example 5 Metabolic Stability Test in Liver Microsomes

Materials:

Male CD1 mouse liver microsomes was supplied by Research Institute forLiver Diseases (Shanghai) Co., Ltd. Male SD rat liver microsomes wassupplied by BioreclamationIVT in US.

Phenacetin, glucose-6-phosphate (G-6-P), glucose-6-phosphatedehydrogenase (G-6-PD), and nicotinamide adenine dinucleotide phosphate(NADP) were supplied by Sigma-Aldrich (Missouri, USA).

Solution Preparation:

10 mM stock solution of test compound: Certain amount of test compoundwas weighed and dissolved in certain volume of dimethylsulfoxide (DMSO)to get the stock solution of test compound at 10 mM.

Reaction termination solution: Certain amount of phenacetin as internalstandard was weighed and dissolved in acetonitrile to get the reactiontermination solution at 1000 ng/mL, and stored at room temperature foruse.

Experimental Method:

The stock solution of test compound was diluted to the designatedconcentration with organic solution (usually the mixtures ofacetonitrile, methanol and water with different portions depending onthe compound solution) to make the final concentration to be 1 μM andthe contents of organic solvents no more than 1% (For DMSO, thecontrolled margin was 0.1%) in the final incubation system. 100 mM NADP,500 mM G-6-P and 100 U/mL G-6-PDH were mixed and diluted with ultrapurewater to provide the NADPH regenerating system containing 1 mM NADP, 5mM G-6-P and 1 U/mL G-6-PD, which was pre-incubated at 37° C. water-bathfor 10 min and then cooled on ice until being added into the reactionsystem. 20 mg/mL liver microsomes was mixed with 200 mM PBS and dilutedwith ultrapure water to make the concentrations of liver microsomes andPBS to be 0.5 mg/mL and 50 mM in the final incubation system,respectively. After the diluted liver microsomes was mixed with theNADPH regenerating solution, certain volumes of 100 mM EDTA and 300 mMMgCl₂ (concentration of EDTA and MgCl₂ in the final incubation system is1 mM and 3 mM, respectively) were added, and the incubation system wasput into 37° C. water bath. The incubation was commenced by adding thestock solution of test compound and maintained for 30 min. Theincubation was terminated by adding the reaction termination solution.The 0 min sample was prepared by adding the reaction terminationsolution to the incubation system immediately prior to putting thesystem into the water bath with the addition of the stock solution oftest compound. The terminated incubation mixtures were vortexed andcentrifuged at 4400 rpm for 10 min, and the supernatant was collectedfor LC-MS/MS analysis.

Analytical Method:

The concentration of test compound was determined using LC-MS/MS method.Using the peak area ratio of the compound and the internal standard asan index, the percentage of remaining compound after incubation for 30minutes as compared with the 0 minute sample was calculated, and themetabolic stability of the compound was evaluated.

According to the above tests, the compounds of the invention showed goodmetabolic stability. The metabolic stability of some exemplary compoundsof the invention is as follows:

Rat liver Mouse liver microsome microsome Compound stability stability 173.8% 83.5% 2 99.0% 83.8% 4 62.9% 82.1% 5 76.8% 58.6% 6 70.0% 76.3% 750.3% 49.8% 11 87.6% 80.3% 18 91.5% 82.7% 19 83.8% 66.2% 82 92.9% 93.1%83 96.6% 83.7% 84 67.8% 78.9% 85 78.1% 64.0% 87 97.9% 88.5% 90 82.4%80.9% 91 86.6% 70.5% 94 82.6% 65.4% 95 74.8% 80.1% 97 98.5% 89.5% 9899.2% 83.7% 101 88.0% 84.6% 102 92.7% 86.2% 103 89.7% 78.5% 105 84.0%67.3% 109 85.4% 58.8% 124 74.1% 44.1% 126 79.8% 58.2% 127 49.8% 28.7%128 34.0% 15.9% 147 65.0% 48.1% 149 66.8% 59.7% 153 41.7% 46.9% 17745.9% 31.0% 196 100.0% 95.2% 197 99.5% 98.4% 201 91.6% 79.3% 202 94.2%96.4% 203 92.1% 91.3% 211 98.8% 99.7% 227 88.8% 81.4% 232 86.6% 76.3%235 89.0% 75.5% 236 91.3% 83.9% 239 93.0% 91.8% 249 98.0% 100.0% 254100.0% 90.9% 259 95.1% 86.9% 262 98.3% 92.2% 266 98.2% 91.5% 291 100.0%98.9%

Example 6 Determination of Solubility

1. Preparation of Sample Solution

-   -   Sample standard solution: About 3-5 mg test compound was        accurately weighed and added into a 5 mL sample tube, 5 mL DMSO        was added. Shaking and sonicating for 1 hour.    -   pH 2.1 sample solution: About 1 mg test compound was accurately        weighed and added into a 1 mL sample tube, 1 mL pH 2.1 sodium        phosphate buffer was added. Shaking. Adding test compound to the        solution, if the solution is visually clear, till there is        obvious insoluble in the solution. Sonicating for 1 hour.    -   pH 7.4 sample solution: About 1 mg test compound was accurately        weighed and added into a 1 mL sample tube, 1 mL pH 7.4 sodium        phosphate buffer was added. Shaking. Adding test compound to the        solution, if the solution is visually clear, till there is        obvious insoluble in the solution. Sonicating for 1 hour.

2. Determination

-   -   1 mL sample standard solution was accurately pipetted into a        HPLC tube. The peak area was determined by HPLC.    -   0.5 mL pH 2.1 sample solution was filtered by syringe filter and        was accurately pipetted into a HPLC tube, and 0.5 mL pH 2.1        sodium phosphate buffer was accurately added. Shaking. The peak        area was determined by HPLC.    -   0.5 mL pH 7.4 sample solution was filtered by syringe filter and        was accurately pipetted into a HPLC tube, and 0.5 mL pH 7.4        sodium phosphate buffer was accurately added. Shaking. The peak        area was determined by HPLC.    -   HPLC condition:    -   Instrument: Agilent 1200    -   Column: Agilent SB-C18 5 u 4.6*150 mm    -   Mobile phase:        -   Phase A: Water (containing 0.1% formic acid)        -   Phase B: MeOH (containing 0.1% formic acid)

Gradient table Time (min) % A % B 0 95 5 10 5 95 13 5 95 14 95 5 16 95 5

3. Calculation

-   -   The solubility of the test compound in pH 2.1 and pH 7.4 sodium        phosphate buffers were calculated by the following formulae:

Sample solubility at pH 2.1 (mg/mL)=2×A×Y÷X

Sample solubility at pH 7.4 (mg/mL)=2×A×Z÷X

-   -   wherein:        -   A: The concentration of the test compound in sample standard            solution, mg/mL;        -   X: The peak area of sample standard solution;        -   Y: The peak area of pH 2.1 sample solution;        -   Z: The peak area of pH 7.4 sample solution.

The solubilities of some exemplary compounds of the invention are asfollows:

Solubility (mg/mL) Compound pH 2.1 pH 7.4 3 >1.000 0.716 9 >1.000 0.08520 0.570 0.062 68 0.141 <0.005 71 0.064 0.055 82 0.146 0.037 97 0.0770.021 102 0.729 <0.005 125 0.448 0.019 219 0.190 0.060 223 0.060 0.016243 0.055 <0.005 249 0.036 0.011 262 0.237 0.013 271 0.974 0.124 2840.789 0.818

1. A compound of formula (I):

and/or a pharmaceutically acceptable salt thereof, and/or solvates,racemic mixtures, enantiomers, diasteromers, and tautomers thereof,wherein A is chosen from

wherein, R₇ is chosen from H, halo, —CN, —OH, or —NH₂ R₁ is chosen fromH, —OH, halo, C₁₋₆ alkyl, C₁₋₆ alkoxyl, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)₂, oxo, or C₃₋₈ cycloalkyl; each of R₂ is independently chosenfrom H, deuterium, halo, —OH, —NH₂, —CN, —SH, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, oxo, —OR₅, —OCOR₅, —NHR₅,—N(R₅)(C₁₋₄ alkyl), —COR₅, —NHCOR₅, or 3-8 membered heterocyclylcontaining one or more heteroatoms independently chosen from N, O, andS; in which each of said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl or 3-8 membered heterocyclyl containing one or moreheteroatoms independently chosen from N, O, and S is optionallysubstituted with one or more groups chosen from deuterium, halo, —CN,—OH, —SH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, or C₁₋₆ alkoxyl; ortwo R₂, which attach to the same carbon atom, together with the carbonatom they are attached to form a 3-5 membered cycloalkyl which isoptionally substituted with one or more halo or deuterium; R_(3′) andR_(4′) are both H; R₃ and R₄ are independently chosen from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, 3-12 memberedheterocyclyl containing one or more heteroatoms independently chosenfrom N, O, and S, phenyl, 5-12 membered heteroaryl containing one ormore heteroatoms independently chosen from N, O, and S, —C(O)R₅, —OR₅,or —NHR₅, in which each of said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₂ cycloalkyl, 3-12 membered heterocyclyl containing one or moreheteroatoms independently chosen from N, O, and S, phenyl, or 5-12membered heteroaryl containing one or more heteroatoms independentlychosen from N, O, and S is optionally substituted with one or more R₆;provided that R₃ and R₄ are not H simultaneously; provided that when oneof R₃ and R₄ is optionally substituted phenyl or optionally substituted5-6 membered heteroaryl containing one or more heteroatoms independentlychosen from N, O, and S, the other one is —OR₅ or —NHR₅; or R₃ andR_(3′) are independently chosen from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₂ cycloalkyl, 3-12 membered heterocyclyl containing one ormore heteroatoms independently chosen from N, O, and S, phenyl, 5-12membered heteroaryl containing one or more heteroatoms independentlychosen from N, O, and S, —C(O)R₅, —OR₅, or —NHR₅, in which each of saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, 3-12 memberedheterocyclyl containing one or more heteroatoms independently chosenfrom N, O, and S, phenyl, or 5-12 membered heteroaryl containing one ormore heteroatoms independently chosen from N, O, and S is optionallysubstituted with one or more R₆; R₄ and R_(4′) together with the N atomthey are attached to form a 3-8 membered heterocyclic ring containingone or more heteroatoms independently chosen from N, O, and S which isoptionally substituted by one or more R₆; R₅ is chosen from C₁₋₆ alkylor C₃₋₈ cycloalkyl, each of which is optionally substituted with one ormore groups independently chosen from halo, —CN, —OH, —SH, —NH₂, or C₁₋₆alkoxyl; each of R₆ is independently chosen from deuterium, halo, —CN,—OH, —SH, —NH₂, C₁₋₆ alkoxyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, 3-8 membered heterocyclyl containing one or more heteroatomsindependently chosen from N, O, and S, phenyl, or 5-6 memberedheteroaryl containing one or more heteroatoms independently chosen fromN, O, and S, in which each of said C₁₋₆ alkoxyl, C₁₋₆ alkyl, C₃₋₈cycloalkyl, 3-8 membered heterocyclyl containing one or more heteroatomsindependently chosen from N, O, and S, phenyl, or 5-6 memberedheteroaryl containing one or more heteroatoms independently chosen fromN, O, and S is optionally substituted with one or more groupsindependently chosen from halo, —CN, —OH, —SH, —NH₂, C₁₋₆ alkoxyl, C₂₋₆alkynyl, or C₁₋₆ alkyl; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, or
 2. 2.The compound of formula (I) according to claim 1, or a pharmaceuticallyacceptable salts thereof, and/or solvates, racemic mixture, enantiomers,diasteromers, and tautomers thereof, wherein, R₁ is chosen from H, —OHor halo.
 3. The compound of formula (I) according to claim 2, or apharmaceutically acceptable salts thereof, and/or solvates, racemicmixture, enantiomers, diasteromers, and tautomers thereof, wherein, R₁is —OH.
 4. The compound of formula (I) according to claim 1, or apharmaceutically acceptable salts thereof, and/or solvates, racemicmixture, enantiomers, diasteromers, and tautomers thereof, wherein, eachof R₂ is independently chosen from H, deuterium, halo, —OH, —NH₂, —CN,—SH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, oxo, —OR₅, —OCOR₅, —NHR₅, —N(R₅)(C₁₋₄ alkyl), —NHCOR₅, or3-8 membered heterocyclyl containing one or more heteroatomsindependently chosen from N, O, and S.
 5. The compound of formula (I)according to claim 4, or a pharmaceutically acceptable salts thereof,and/or solvates, racemic mixture, enantiomers, diasteromers, andtautomers thereof, wherein, each of R₂ is independently chosen from H,deuterium, halo, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.
 6. The compound offormula (I) according to claim 1, or a pharmaceutically acceptable saltsthereof, and/or solvates, racemic mixture, enantiomers, diasteromers,and tautomers thereof, wherein, R₃ and R₄ are independently chosen fromC₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, 3-12 membered heterocyclyl containing oneor more heteroatoms independently chosen from N, O, and S, phenyl, 5-12membered heteroaryl containing one or more heteroatoms independentlychosen from N, O, and S, —C(O)R₅, —OR₅, or —NHR₅, in which each of saidC₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, 3-12 membered heterocyclyl containing oneor more heteroatoms independently chosen from N, O, and S, phenyl, or5-12 membered heteroaryl containing one or more heteroatomsindependently chosen from N, O, and S is optionally substituted with oneor more R₆.
 7. The compound of formula (I) according to claim 6, or apharmaceutically acceptable salts thereof, and/or solvates, racemicmixture, enantiomers, diasteromers, and tautomers thereof, wherein, R₃and R₄ are independently chosen from C₁₋₆ alkyl substituted with one ormore halo, 5-12 membered heteroaryl containing one or more heteroatomsindependently chosen from N, O, and S substituted with C₁₋₆ haloalkyl,or —OR₅.
 8. The compound of formula (I) according to claim 1, or apharmaceutically acceptable salts thereof, and/or solvates, racemicmixture, enantiomers, diasteromers, and tautomers thereof, wherein, R₅is C₁₋₆ alkyl optionally substituted with one or more halo.
 9. Thecompound of formula (I) according to claim 1, or a pharmaceuticallyacceptable salts thereof, and/or solvates, racemic mixture, enantiomers,diasteromers, and tautomers thereof, wherein, each of R₆ isindependently chosen from deuterium, halo, —CN, —OH, —NH₂, C₁₋₆ alkoxyl,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclylcontaining one or more heteroatoms independently chosen from N, O, andS, phenyl, or 5-6 membered heteroaryl containing one or more heteroatomsindependently chosen from N, O, and S, in which each of said C₁₋₆alkoxyl, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclylcontaining one or more heteroatoms independently chosen from N, O, andS, phenyl, or 5-6 membered heteroaryl containing one or more heteroatomsindependently chosen from N, O, and S is optionally substituted with oneor more halo.
 10. The compound of formula (I) according to claim 1, or apharmaceutically acceptable salts thereof, and/or solvates, racemicmixture, enantiomers, diasteromers, and tautomers thereof, wherein nis
 1. 11. The compound of formula (I) according to claim 1, or apharmaceutically acceptable salts thereof, and/or solvates, racemicmixture, enantiomers, diasteromers, and tautomers thereof, wherein, R₃is chosen from H, C₁₋₆ alkyl optionally substituted by C₁₋₆ haloalkyl,or 5-12 membered heteroaryl containing one or more heteroatomsindependently chosen from N, O, and S optionally substituted by C₁₋₆haloalkyl; R_(3′) is H; R₄ and R_(4′) together with the N atom they areattached to form a 3-8 membered heterocyclic ring containing one or moreheteroatoms independently chosen from N, O, and S optionally substitutedby one or more groups chosen from halo, —OH, or C₁₋₆ haloalkyl.
 12. Thecompound of formula (I) according to claim 1, or a pharmaceuticallyacceptable salts thereof, and/or solvates, racemic mixture, enantiomers,diasteromers, and tautomers thereof, wherein, the compound of formula(I) is chosen from

wherein X is halo.
 13. The compound of formula (I) according to am claim1, or a pharmaceutically acceptable salts thereof, and/or solvates,racemic mixture, enantiomers, diasteromers, and tautomers thereof,wherein, the compound of formula (I) has the structure of formula (II);wherein X is halo; p is 0, 1, or 2; m is 0, 1, or 2;


14. The compound of formula (I) according to claim 13, or apharmaceutically acceptable salts thereof, and/or solvates, racemicmixture, enantiomers, diasteromers, and tautomers thereof, wherein, thecompound of formula (I) is chosen from

wherein, X is halo; p is 0, 1, or 2; m is 0, 1, or
 2. 15. The compoundof formula (I) according to claim 14, or a pharmaceutically acceptablesalts thereof, and/or solvates, racemic mixture, enantiomers,diasteromers, and tautomers thereof, wherein, the compound of formula(I) has the structure of formula (II-1); wherein X is halo; p is 0, 1,or 2; m is 0, 1, or 2;


16. A compound selected from: Compound Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51  52  53  55  56  57

 59

 60

 61

 62

 63

 64

 65

 66

 67

 68

 69

 71

 72

 73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 87

 89

 90

 91

 92

 93

95 & 96

97 & 98

 99

100 & 101

102 & 103

104 & 105

106 & 107

108 & 109

110 & 111

112 & 113 114 & 115 116 & 117 118 & 119

120 & 121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146 & 147

148 & 149

150 & 151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

186

187

188

189

190

191

192

193

194

195

199

200

201 & 202

203 204 205 206 207

209

212

213

214

215

216

217

218

219

220

221

222 & 223

224

225

226

227

228

229

230 & 231

232

233

235

236 & 237

238

239

240

241

242

243

246 & 247

251 & 252

253 & 254

259

260

261 262 & 263 264 & 265 266 267 268 269

270

271

272 & 273

274

275

276

277

278

279

280

281

282

283

284

285 & 286

287 & 288

289 & 290

291 & 292

293

294

295

296

297

298

299

300

301

or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition comprising the compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and optionally comprising at least onepharmaceutically acceptable excipient.
 18. A method of treating adisease induced by IDH mutation in a subject, comprising administeringthe compound according to claim 1 or a pharmaceutically acceptable saltthereof to the subject.
 19. The method of claim 18, wherein the diseaseinduced by IDH mutation is cancer, which is chosen from solid tumors,neurogliocytoma, or hematological malignant tumor.
 20. The method ofclaim 19, wherein, the cancer is chosen from acute myeloid leukemia(AML), acute promyelocytic leukemia (APL), glioblastoma (GBM),myelodysplastic syndrome (MDS), myeloproliterative neoplasms (MPN),cholangiocarcinoma, chondrosarcoma, giant cell tumor, intestinal cancer,melanoma, lung cancer, or non-Hodgkin's lymphoma (NHL).
 21. A compoundof formula (IV),

and a racemic mixture or enantiomers thereof, wherein R₁ is —OH or oxo,R₂ and m are defined as in claim 1; R_(a) is chosen from halo,—OS(O)₂CF₃, —B(OH)2, —B(OC1-6 alkyl)2,

R_(b) is H or C1-6 alkyl.
 22. The compound of formula (I) according toclaim 1, or a pharmaceutically acceptable salts thereof, and/orsolvates, racemic mixture, enantiomers, diasteromers, and tautomersthereof, wherein, R₃ and R₄ are independently chosen from C₁₋₆ alkylsubstituted with one or more halo.
 23. The method of claim 19, whereinthe cancer is chosen from leukemia, lymphoma, or myeloma.
 24. The methodof claim 20, wherein the cancer is intrahepatic cholangiocarcinoma(IHCC).
 25. The compound of formula (IV) according to claim 21, whereinthe compound of formula (IV) has the structure of formula (IV-1),wherein m is 0, 1, or 2;


26. The compound of formula (IV) according to claim 21, wherein thecompound of formula (IV) has the structure of formula (IV-2), wherein Xis halo; m is 0, 1, or 2;


27. The compound of formula (IV) according to claim 21, wherein thecompound of formula (IV) has the structure of formula (IV-3), wherein Xis halo; p is 0, 1, or 2; m is 0, 1, or 2;


28. The compound of formula (IV) according to claim 21, wherein thecompound of formula (IV) is chosen from: